Environmental Health Risks
Information on EPA's Draft Reassessment of Dioxins Gao ID: GAO-02-515 April 26, 2002Dioxins--chemical compounds that share structural and biological characteristics--have been linked to human illnesses, including cancer. Often the byproducts of combustion and industrial processes, complex mixtures of dioxins enter the food chain and human diet through emissions into the air. The Environmental Protection Agency (EPA) and the World Health Organization (WHO) noted the potential human health risks of dioxins in the 1970s when animal studies showed them to be among the most potent cancer-causing chemicals. EPA derived its estimates of human dietary exposure to dioxins in the United States from (1) chemically analyzed samples of 10 food types, (2) toxicity estimates of levels of individual dioxins in these foods, and (3) estimates of the quantities of these foods consumed by Americans. To develop more reliable national estimates of dietary exposure, EPA incorporated into its analysis some food studies that were nationally representative. Although both EPA and the WHO have assessed the human health risks of dioxins during the last decade, some of their objectives and processes have differed. Nonetheless, the analytical methods used and the conclusions reached have much in common. A major difference in the assessments is whether there are threshold levels below which exposure to dioxins would pose a negligible risk of cancer. EPA assumed there is no safe threshold level for cancer effects, but the WHO assumed there is. EPA's draft reassessment report reflects the recommendations and suggestions provided to the agency by the two most recent independent peer review panels. The panels, one consisting of 12 independent reviewers and the other convened by EPA's Science Advisory Board, concurred with many key assumptions and approaches that EPA used.
GAO-02-515, Environmental Health Risks: Information on EPA's Draft Reassessment of Dioxins
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United States General Accounting Office:
GAO:
Report to Congressional Requesters:
April 2002:
Environmental Health Risks:
Information on EPA's Draft Reassessment of Dioxins:
GAO-02-515:
Contents:
Letter:
Results in Brief:
Background:
EPA Used Data on the Presence of Dioxins, Toxicity, and Food
Consumption to Estimate Human Dietary Exposure:
EPA's and WHO's Specific Reassessment Objectives and Processes
Differed, but Their Analytical Methods and Conclusions on Dioxins'
Health Risks Are Similar:
EPA's Draft Dioxin Reassessment Report Generally Reflects the Views of
Recent Peer Reviews:
Observations:
Agency Comments and Our Response:
Scope and Methodology:
Appendix I: Major Milestones in the EPA and WHO Dioxin Risk Assessment
Efforts:
Appendix II: Comparison of the Major Conclusions from EPA's and WHO's
Dioxin Risk Assessments:
Appendix III: Questions EPA Asked Peer Review Panels to Address:
Appendix IV: EPA's Responses to Peer Review Panels:
Appendix V: Comments from the Environmental Protection Agency:
Appendix VI: GAO Contacts and Staff Acknowledgments:
Tables:
Table 1: EPA's Estimates of the Average U.S. Adult's Daily Exposure to
Dioxins From Dietary Intake, Picograms per Day:
Table 2: Numbers, Types, and Dates of Food Samples EPA Used in
Estimating Dietary Exposure to Dioxins:
Table 3: Numbers, Types, and Dates of Food Samples EPA Used in
Estimating Dietary Exposure to PCBs in Four Food Categories:
Table 4: EPA's Estimates of Toxic Concentrations of Dioxins in 10 Food
Categories, Picograms per Gram:
Table 5: Estimated Daily Dietary Intake of 10 Food Types for an
American Adult Weighing 70 Kilograms (154 pounds):
Table 6: Questions for the July 2000 Panel Review of EPA's Draft
Dioxin Reassessment:
Table 7: Questions for the November 2000 Science Advisory Board Panel:
Table 8: EPA's Responses to July 2000 Panel's Report:
Table 9: EPA's Responses to Science Advisory Board Panel's Comments:
Abbreviations:
CDD: polychlorinated dibenzo-p-dioxins:
CDF: polychlorinated dibenzofurans:
ED: effective dose:
EPA: Environmental Protection Agency:
IARC: International Agency for Research on Cancer:
PCB: polychlorinated biphenyls:
TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin:
TEF: toxic equivalency factors:
TEQ: toxic equivalency:
USDA: Department of Agriculture:
WHO: World Health Organization:
[End of section]
United States General Accounting Office:
Washington, DC 20548:
April 26, 2002:
The Honorable John Breaux:
The Honorable Thad Cochran:
United States Senate:
Some dioxins, which are chemical compounds that share certain
structural and biological characteristics, have been linked to adverse
human health effects, including cancer.[Footnote 1] Often the
byproducts of combustion and industrial processes, complex mixtures of
dioxins enter the food chain and human diet through emissions into the
air that settle on soil, plants, and water. The Environmental
Protection Agency (EPA) and other entities, such as the World Health
Organization, began assessing the potential human health risks of
dioxins in the 1970s, when animal studies on one of them-2,3,7,8-
tetrachlorodibenzo-p-dioxin, or TCDD”showed it to be the most potent
cancer-causing chemical studied to date. EPA's initial assessment of
dioxins was published in 1985. Since that time, there have been major
advances in the scientific understanding of dioxin toxicity and
significant new studies on dioxins' potential adverse health effects.
As a result, in 1991 EPA decided to conduct a reassessment of the
health risks of exposure to dioxins. A draft of this reassessment was
reviewed by a scientific peer review panel in 1995, and three panels
reviewed key segments of later drafts in 1997 and 2000.
EPA plans to release its comprehensive reassessment report on the
health risks of dioxins this year. According to EPA officials, the
report will conclude that dioxins may adversely affect human health at
lower exposure levels than previously thought and that most exposure
to dioxins occurs from eating such American dietary staples as meats,
fish, and dairy products, which contain minute traces of dioxins.
These foods contain dioxins because animals eat plants and commercial
feed, and drink water, contaminated with dioxins, which then
accumulate in animals' fatty tissue. EPA plans to use its reassessment
of the risks posed by dioxins to develop a risk management strategy to
address the health risks identified and to determine whether the
nation's current air, water, and hazardous waste cleanup programs need
to be changed to protect the public health. EPA's reassessment will be
considered by the National Academies[Footnote 2] in an ongoing study
of the implications of dioxin in the food supply, which is examining,
among other things, options to reduce dietary exposure to dioxins.
Of the several hundred known dioxins, 29 are considered toxic to
varying degrees. TCDD is the most widely studied dioxin and one of the
most toxic. EPA's reassessment report on the human health risks posed
by dietary exposure to dioxins evaluates the health effects of TCDD
and the 28 other compounds with similar structural and biological
characteristics and varying toxic effects. According to EPA, its
evaluation of the effects of these compounds is sufficient to
characterize the effects of environmental dioxins in general.
Concerned about the potentially significant impact that EPA's dioxin
risk assessment report could have on consumers and on the food and
agriculture industries, you asked us to examine several aspects of
EPA's reassessment of dioxins. As agreed with your offices, this
report describes (1) the data EPA used to estimate human dietary
exposure to dioxins in the United States; (2) how EPA's reassessment
objectives, processes, analytical methods, and conclusions on the
health risks posed by dioxins compare with those of the World Health
Organization; and (3) the extent to which the draft dioxin
reassessment report reflects the views of independent peer review
panels that reviewed key aspects of the reassessment. Also as agreed
with your offices, our report provides information on the relevant
scientific issues but does not render an opinion on the scientific
merits of the reassessment. This report is based primarily on EPA's
draft reassessment report dated October 2001,[Footnote 3] which EPA
circulated for internal agency review, and on the two most recent peer
reviews of key segments of the draft reassessment in 2000.
Results in Brief:
EPA derived its estimates of human dietary exposure to dioxins in the
United States from (1) various studies that chemically analyzed
samples of 10 food types, (2) toxicity estimates of the various levels
of the individual dioxins in these foods, and (3) estimates of the
quantities of these foods consumed by Americans. To develop more
reliable national estimates of dietary exposure, EPA incorporated into
its analysis some food studies that were designed to be nationally
representative. However, as EPA notes in its draft reassessment
report, the food data were limited in several ways. In some cases, the
food sampling methods, or the number of samples collected, were not
sufficient to reliably estimate average, nationally representative
exposures. In other cases, the studies did not analyze the food
samples for the presence of all the dioxins that EPA was assessing.
Further, most of the samples were collected 5 or more years ago;
therefore, they may not reflect current exposures if, as EPA believes,
emissions of dioxins have continued to decline in the United States
since 1995 because of air quality regulations. Nonetheless, EPA
believes that its estimate of average dietary exposure to dioxins is a
reasonable characterization of current exposure because, for example,
the emission reductions that have occurred since most of the food
samples were collected are not believed to be as significant as
earlier emission reductions. Regarding toxicity estimates, because
sufficient data are not available on many of the individual dioxins,
EPA used an approach that relies on data developed by the World Health
Organization to estimate the toxicity of the various mixtures of
dioxins identified in the 10 types of foods. Although this approach
may overstate or understate the concentrations of dioxins in the
foods, it is the internationally accepted scientific method for risk
assessments of dioxins.
While both EPA and the World Health Organization have taken steps
during the past decade directed at the general objective of assessing
the human health risks of dioxins, some of their specific objectives
and processes have differed. Nonetheless, the analytical methods the
organizations used and the conclusions they reached have much in
common. EPA established a long-range objective of characterizing the
potential human health risks posed by exposure to dioxins using a
comprehensive, multiyear review process resulting in a reassessment
report. In contrast, the World Health Organization conducted a series
of individual reviews with more narrowly focused primary objectives,
such as updating the estimated amount of dioxins to which a person
could be exposed daily for a lifetime without appreciable health
consequences. Regarding analytical methods and conclusions, both EPA
and the World Health Organization:
* Examined similar sets of human and animal study data, considered a
similar range of health effects, and applied some analytical concepts
that both entities determined were more appropriate to the assessment
of dioxins than those often used in assessments of other chemicals.
* Concluded that dioxins could adversely affect human health at lower
exposure levels than previously thought and that some adverse
noncancer effects, such as reproductive and developmental impairments,
could occur at or near the levels to which the general population is
now being exposed.
A major difference in the organizations' assessments concerns whether
there are threshold levels below which exposure to dioxins would pose
a negligible risk of cancer. While EPA assumed there is no safe
threshold level for cancer effects, the World Health Organization
assumed there is.
EPA's draft reassessment report largely reflects the recommendations
and suggestions provided to the agency by the two most recent
independent peer review panels, although some areas of disagreement on
key scientific issues remain. The panels, one consisting of 12
independent reviewers and the other convened by EPA's Science Advisory
Board, concurred with many key assumptions and approaches that EPA
used. In addition, the panels made recommendations on several issues
and provided suggestions for EPA to consider. EPA generally addressed
the panels' recommendations and suggestions by, for example,
performing additional analyses or explaining that the data currently
available are not yet sufficient to address the recommendation or
suggestion. If EPA disagreed with the panels' recommendations or
suggestions, it explained its position in the text. Additional changes
are being made as EPA prepares the draft for external interagency
review. Lack of consensus on some scientific issues, such as whether
the weight of evidence supports EPA's classification of TCCD as a
human carcinogen, reflects uncertainty in areas where data are
limited. Accordingly, the Science Advisory Board views this
reassessment report as an interim evaluation that will need to be
updated and peer reviewed in the future as important data gaps are
addressed.
Background:
Dioxins persist for a long time in the environment because they do not
dissolve in water and are relatively immobile in soil and sediment.
When animals consume plants, feed, and water contaminated with
dioxins, they accumulate in the animals' fatty tissue. Similarly, when
humans consume these animals, the dioxins then accumulate in human
fatty tissue. According to EPA, because dioxins also persist in the
body for years, recent significant reductions in dioxin emissions into
the air are unlikely to reduce human health risks in the near term.
While EPA estimates that most exposure to dioxins occurs from eating
commonly consumed foods, the draft reassessment report also estimates
that limited exposure to dioxins results from breathing air containing
trace amounts of dioxins; inadvertently ingesting soil containing
dioxins; and absorbing through the skin minute levels of dioxins
present in the soil. Some people may experience higher exposure levels
than the general population as a result of food contamination
incidents; workplace exposures; industrial accidents; or consuming
unusually high levels of fish, meat, or dairy products. When
calculating human exposures, dioxins are measured in picograms”that
is, trillionths (0.000000000001) of a gram. Highly sophisticated
measurement techniques and technologies are required to test foods for
the presence of the 29 dioxins identified as having toxic effects.
The several hundred known dioxin compounds can be placed in one of
three closely related families: polychlorinated dibenzo-p-dioxins
(CDD), polychlorinated dibenzofurans (CDF), and polychlorinated
biphenyls (PCBs). CDDs and CDFs are byproducts of combustion and some
industrial processes. According to EPA, U.S. emissions of CDDs and
CDFs into the environment declined by 75 percent between 1987 and 1995
primarily as a result of reductions in emissions from municipal and
medical waste incinerators. Some PCBs share certain characteristics
with CDDs and CDFs and therefore are identified as "dioxin-like." PCBs
were at one time manufactured for use in products such as lubricants
and industrial transformers but have not been made in the United
States since 1977. However, because dioxins break down so slowly, past
emissions remain in the environment for years”even decades”before they
diminish. Consequently, a large part of humans' current exposure to
dioxins is due to releases of dioxins that were stored in soil and
sediment, and to a lesser extent in vegetation and the atmosphere.
These sources are called "reservoir sources." EPA believes that with
the reduction in current emissions from combustion and incineration,
these reservoir sources have taken on more significance.
According to EPA, dioxins always occur in the environment and in
humans as complex mixtures of individual compounds. However, the
complex nature of the dioxin mixtures to which people are exposed
(through foods or other sources) complicates evaluation of the health
risks such mixtures might pose. Scientists therefore developed the
concept of toxic equivalency factors (TEFs) to facilitate risk
assessment of exposure to these mixtures. Because TCDD is the best-
understood dioxin, it is used as a frame of reference for estimating
the toxicity of the other dioxins, and its TEF is set at 1.0. Only 1
of the other 28 dioxins included in EPA's reassessment has a TEF of
1.0; most of the others have TEFs of 0.1 or less, meaning that they
are considered less toxic to humans than TCDD. International experts
review and periodically update the TEFs based on new data. For its
reassessment of dioxins, EPA used the latest revisions that were made
at an expert meeting organized by the World Health Organization in
1997.[Footnote 4]
Since 1991, EPA has been updating its initial 1985 report assessing
the health risks of dioxins. The October 2001 draft reassessment
report exceeds 3,000 pages. Part I of the draft report provides
information on exposure to dioxins, including chapters on dietary
intake; part II addresses health assessment methodologies and specific
health effects; and part IA the Integrated Summary[Footnote 5]
highlights information in parts I and II on exposure and health
effects and provides a risk characterization”a statement summarizing
EPA's assessment of the health risks associated with dioxins. In the
reassessment, EPA studied the risks of cancer as well as noncancer
health effects, such as neurological and reproductive impairments.
Founded in 1948, the World Health Organization (WHO) is a specialized
agency of the United Nations, with 191 member states. WHO's functions
include giving worldwide guidance in the field of health and setting
global standards for health. WHO carries out these functions through a
variety of offices and programs that often collaborate with each other
and with other public health entities of WHO's member states and
nongovernmental organizations. The principal contributors to the WHO
reassessments of dioxin risks that are discussed in this report have
been (1) the International Agency for Research on Cancer, which
coordinates and conducts both epidemiological and laboratory research
into the causes of cancer; (2) the WHO European Centre for Environment
and Health, which coordinates comprehensive efforts, in collaboration
with the International Programme on Chemical Safety, to evaluate the
possible health risks of dioxins as well as methods of prevention and
control of environmental exposure of the general population to these
chemicals;[Footnote 6] and (3) the Joint Expert Committee on Food
Additives of the United Nations' Food and Agriculture Organization and
WHO, which provides scientific evaluations as a basis for the
development of food standards by the Codex Alimentarius (food code)
Commission.[Footnote 7]
EPA Used Data on the Presence of Dioxins, Toxicity, and Food
Consumption to Estimate Human Dietary Exposure:
To estimate dietary exposure to dioxins, EPA obtained and reviewed
information on (1) the dioxins present in 10 types of foods[Footnote
8] with high fat content, (2) the toxicity of individual dioxins
contained in these food types, and (3) the quantities of these foods
that people in the United States typically eat. EPA has incorporated
new studies following improvements in analytical capabilities to
detect dioxins in food during the 1990s. However, in its draft
reassessment report, EPA identified a number of limitations with the
food data used to estimate dietary exposure that add uncertainty to
the agency's overall estimate of current average daily dietary
exposure to dioxins. For example, in some cases, the studies available
on the presence of dioxins in foods were not designed to estimate
national averages. Further, while EPA used the accepted method for
estimating the toxicity of the dioxins found in the 10 food types, EPA
and others acknowledge that the method has limitations. Finally, EPA
estimated the quantities of these foods consumed using U.S. Department
of Agriculture (USDA) data on U.S. adults' food consumption based on
surveys made between 1989 and 1991; however, EPA believes the dietary
habits of Americans have changed very little over the course of the
past decade.
EPA Estimates That Most Human Exposure to Dioxins Occurs from Eating
Certain Types of Foods:
A body of scientific research on foods in Europe, North America, and
other locations indicates that the primary source of human exposure to
dioxins is the dietary intake of foods, especially those containing
animal fat. According to EPA's October 2001 draft reassessment report,
the average adult in the United States receives about 95 percent of
his or her exposure to dioxins by eating commonly consumed foods, such
as beef, pork, and poultry; fish; and dairy products. (EPA estimated
small exposures to dioxins from the air and soil as well.)
The 10 types of foods EPA analyzed for its reassessment are beef;
pork; poultry; other meats, such as lamb and baloney; eggs; milk;
dairy products, such as cheese and yogurt; freshwater fish and
shellfish; marine fish and shellfish; and vegetable fat, such as corn
and olive oils and margarine. These foods, only one of which is not of
animal origin, are believed to be the major contributors to dietary
exposure to dioxins. Even though vegetable fat products are estimated
to contain low levels of dioxins, EPA included these foods in its
analysis because they are high in fat and common in the American diet.
EPA excluded fruits and vegetables from its analysis because data on
dioxins in U.S. fruit and vegetable products, which generally contain
little or no fat, are extremely limited. The existing data indicate
that typically these products contain low levels of dioxins, which
generally stem from residues”deposits on outer layers with little
penetration to inner portions.
Until recently, chemical analyses of dioxins in foods have focused
primarily on two of the families of dioxins, the CDDs and CDFs, with
less attention on identifying and measuring specific PCBs. The draft
reassessment report includes an evaluation of PCB levels in the 10
food types. The draft report identifies estimated exposures to CDDs
and CDFs together and identifies the estimated exposure to PCBs
separately. This approach provides information that can inform
potential regulatory approaches, among other things, because CDDs and
CDFs result primarily from combustion and industrial processes,
whereas PCBs, which persist in the environment from the 1970s and
earlier, are no longer being manufactured.
As shown in table 1, EPA estimated that the average adult in the
United States is exposed daily to about 63 picograms of dioxins
through dietary intake, with the highest exposure coming from beef and
freshwater fish and shellfish. According to EPA, this exposure level
is close to the level that has caused adverse noncancer effects in
animals, such as effects on the development of reproductive systems.
It is important to note that EPA's dietary exposure estimates are
averages, and they do not apply to adults with additional or unusual
exposure to dioxins-for example, from diets unusually high in fat
content or diets of foods high in dioxin content.[Footnote 9]
Table 1: EPA's Estimates of the Average U.S. Adult's Daily Exposure to
Dioxins From Dietary Intake, Picograms per Day:
Food type: Beef;
Dietary exposure to CDDs and CDFs: 9.0;
Dietary exposure to PCBs: 4.2;
Total dietary exposure to dioxins: 13.2.
Food type: Freshwater fish and shellfish;
Dietary exposure to CDDs and CDFs: 5.9;
Dietary exposure to PCBs: 7.1;
Total dietary exposure to dioxins: 13.0.
Food type: Dairy products (cheese, yogurt, etc.);
Dietary exposure to CDDs and CDFs: 6.6;
Dietary exposure to PCBs: 3.2;
Total dietary exposure to dioxins: 9.8.
Food type: Other meats (lamb, baloney, etc.);
Dietary exposure to CDDs and CDFs: 4.5;
Dietary exposure to PCBs: 1.0;
Total dietary exposure to dioxins: 5.5.
Food type: Marine fish and shellfish;
Dietary exposure to CDDs and CDFs: 2.5;
Dietary exposure to PCBs: 2.4;
Total dietary exposure to dioxins: 4.9.
Food type: Milk;
Dietary exposure to CDDs and CDFs: 3.2;
Dietary exposure to PCBs: 1.5;
Total dietary exposure to dioxins: 4.7.
Food type: Pork;
Dietary exposure to CDDs and CDFs: 4.2;
Dietary exposure to PCBs: 0.2;
Total dietary exposure to dioxins: 4.4.
Food type: Poultry;
Dietary exposure to CDDs and CDFs: 2.4;
Dietary exposure to PCBs: 0.9;
Total dietary exposure to dioxins: 3.3.
Food type: Eggs;
Dietary exposure to CDDs and CDFs: 1.4;
Dietary exposure to PCBs: 1.7;
Total dietary exposure to dioxins: 3.1.
Food type: Vegetable fat (oils, margarine, etc.);
Dietary exposure to CDDs and CDFs: 1.0;
Dietary exposure to PCBs: 0.6;
Total dietary exposure to dioxins: 1.6.
Food type: Total;
Dietary exposure to CDDs and CDFs: 40.7;
Dietary exposure to PCBs: 22.8;
Total dietary exposure to dioxins: 63.5.
Notes: The average adult is assumed to weigh 70 kilograms (154
pounds). A picogram is one-trillionth of a gram.
Source: Derived from U.S. EPA, October 2001 draft dioxin reassessment
report, chapter 4, tables 430 and 4-31.
[End of table]
The Food Samples EPA Studied to Identify the Presence of Dioxins Had a
Variety of Limitations:
To estimate any population's dietary intake of dioxins, the specific
dioxins present in the various foods must be identified and measured
through chemical analyses of the foods. However, reliable estimates of
the average concentrations of dioxins in specific foods nationwide
have only recently begun to be available. In the past, data were
available only from studies of dioxin concentrations in a specific
food product or products in a specific location or a few locations,
and these data were not sufficient to reliably estimate average
national exposure. During the 1990s, as analytical capabilities to
detect dioxins at parts-per-trillion levels were developed, new
studies of foods in the United States, some with broader scope than
the earlier studies, became available. EPA has incorporated new studies
into its analysis of dietary exposure to dioxins to try to develop
more reliable national estimates of such exposure. As a result, the
estimates presented in the October 2001 draft reassessment report are
based on more food data than the drafts developed just a few years ago.
Nevertheless, in its October 2001 draft reassessment report, EPA said
that the amount and the representativeness of the food data it used to
estimate the average U.S. adult's dietary exposure to dioxins vary.
Further, EPA officials acknowledged that some of the available studies
were not designed to estimate national average exposures. As discussed
below, the food sample data are limited in part by the timing of the
sampling, variations in the methods used to collect the samples, and
the types of samples collected and analyzed. In commenting on a draft
of this report, EPA officials said that these food data limitations do
not represent major weaknesses in its estimates of dietary exposure to
dioxins.
* As reported in the draft reassessment, most of the food samples were
collected between 5 and 8 years ago. Current samples would be expected
to have lower dioxin levels because emissions containing dioxins
declined by about 75 percent from 1987 to 1995, and EPA believes the
downward trend is continuing.[Footnote 10] Nevertheless, EPA believes
that the exposure estimates based on food data from the mid-1990s are
representative of current dietary exposure for several reasons. First,
EPA believes that because most of the food samples the agency used for
its reassessment were collected after the 75-percent decrease in
emissions, much of the decrease should already be reflected in the
foods' dioxin concentration numbers. Second, EPA said that, because
most municipal and medical waste incinerators are located far from and
downwind of concentrated meat and dairy production areas, the impact
of any emission reductions since 1995 on the commercial food supply
should be proportionately less than on the environment in general.
Third, EPA said that because reservoir sources of dioxins account for
half or more of current exposure, and because some sources of dioxins
are unknown, it is unlikely that emission reductions that occurred
after most of the food samples were taken would significantly affect
the current estimate of general population exposure from the
commercial food supply.
* According to EPA, while its analyses of some of the foods are based
on national samples collected from food processing or food monitoring
locations, such as federal slaughtering establishments, other analyses
are based on limited "market basket surveys"”random purchases of
selected products, such as eggs, direct from grocery stores”in a small
number of U.S. and Canadian cities.[Footnote 11] Depending on their
design, national surveys would generally be more representative of
average dietary exposures to dioxins than limited surveys.
* Some of the analyses of the foods were derived from individual food
samples, while others were from composite samples. Using composites is
more economical than using individual samples, and EPA believes they
are appropriate for use in analyzing dioxin concentrations to
establish average, or mean, exposure estimates. However, EPA
acknowledges that data on the variability or range of results from
individual samples typically are not available from studies analyzing
composite samples. As a result, information that can provide insight
into the reliability of the estimates is not available. Table 2 shows
the number(s), type(s), and date(s) of the samples EPA used for each
of the 10 food categories.
Table 2: Numbers, Types, and Dates of Food Samples EPA Used in
Estimating Dietary Exposure to Dioxins:
Food type: Beef (back fat samples);
Number/type of sample: 63 individual samples;
Year(s) samples collected: 1994.
Food type: Pork (belly fat samples);
Number/type of sample: 78 individual samples;
Year(s) samples collected: 1995.
Food type: Poultry (abdominal fat samples);
Number/type of sample: 78 individual samples;
Year(s) samples collected: 1996.
Food type: Milk;
Number/type of sample: 8 composite samples;
Year(s) samples collected: 1996 and 1997.
Food type: Dairy products;
Number/type of sample: 8 composite samples;
Year(s) samples collected: 1996 and 1997.
Food type: Eggs[A];
Number/type of sample: 15 composite samples (24 eggs each);
Year(s) samples collected: 1997.
Food type: Marine fish and shellfish[A];
Number/type of sample: 158 individual samples;
Year(s) samples collected: 1995 and 1996.
Food type: Freshwater fish and shellfish[A];
Number/type of sample: 222 samples (individual and composite);
Year(s) samples collected: 1986-89; 1994; 1996-99.
Food type: Vegetable fat (oils, margarine, etc.)[A];
Number/type of sample: 30 individual samples;
Year(s) samples collected: 1995[B].
Food type: Other meats;
Number/type of sample: [C];
Year(s) samples collected: [C].
[A] EPA used these samples to analyze CDDs and CDFs only.
[B] Estimate based on 1996 study publication date.
[C] EPA did not provide this information for other meats.
Source: U.S. EPA, October 2001 draft dioxin reassessment report.
[End of table]
* According to the draft reassessment report, data from some of the
food studies were sufficient to estimate exposure to total dioxins”the
CDDs, CDFs, and PCBs. However, the report shows that in other cases,
the data only provided support for estimating exposure to CDDs and
CDFs. As a result, for four food categories, different studies are
used for estimating exposure to CDDs and CDFs than those used for
PCBs. As reported in the draft reassessment, these studies analyzed
fewer samples, a number of which were collected 14 or more years ago
and therefore provide data on dioxins that may not reflect current
levels. Table 3 shows information on the four foods for which EPA used
different samples to estimate exposure to PCBs than those used to
estimate CDDs and CDFs.
Table 3: Numbers, Types, and Dates of Food Samples EPA Used in
Estimating Dietary Exposure to PCBs in Four Food Categories:
Food type: Eggs;
Number/type of sample: 18 individual samples;
Year(s) samples collected: 1995.
Food type: Eggs;
Number/type of sample: 6 composite samples[A];
Year(s) samples collected: 1986-88[B].
Food type: Marine fish and shellfish;
Number/type of sample: 1 composite of 13 samples;
Year(s) samples collected: 1995.
Food type: Marine fish and shellfish;
Number/type of sample: 5 composites[A];
Year(s) samples collected: 1986-1988.
Food type: Freshwater fish and shellfish;
Number/type of sample: 1 composite of 10 samples;
Year(s) samples collected: 1995.
Food type: Freshwater fish and shellfish;
Number/type of sample: 6 composites[A];
Year(s) samples collected: 1986-88[B].
Food type: Vegetable fat;
Number/type of sample: 5 composites[A];
Year(s) samples collected: 1986-88.
[A] The studies used in the analyses do not specify the number of
individual samples in the composite samples.
[B] The year that one of the composite samples was collected is not
identified. The study was published in 1989.
Source: U.S. EPA, October 2001 draft dioxin reassessment report.
[End of table]
* As EPA acknowledges in the draft report, its analyses of dioxins
present in foods are based on uncooked foods, even though dioxin
levels can be different in cooked and uncooked foods. According to
EPA, while many studies indicate that foods have similar dioxin
concentrations whether they are cooked or uncooked, the studies show
that some foods have lower concentrations of dioxins when they are
cooked, while others have higher levels when they are cooked. These
differences reflect, in part, the fact that different cooking methods
(frying, boiling, grilling, etc.) may have different effects on dioxin
levels. On the basis of the available data, which it believes are not
conclusive, EPA states in the draft reassessment report that uncooked
food is a reasonable surrogate to use for identifying and quantifying
dioxin concentrations in cooked food.
* Because the primary focus of EPA's exposure assessment was on foods
produced and consumed in the United States, EPA's analysis does not
address imported food products that may vary from domestic sources in
dioxin content.
Despite these limitations, the data on dioxin levels in foods
supporting the October 2001 draft report reflect a significant
improvement compared with the data EPA had available for use in its
1994 draft reassessment report, which was peer reviewed in 1995 by
EPA's Science Advisory Board. Specifically, in the 1994 draft, EPA
provided estimates of levels of CDDs and CDFs for seven food types;
the October 2001 draft provided estimates for ten food types. With the
exception of an estimate for fish that was based on 60 samples, the
1994 draft estimates were developed from samples ranging in number
from 2 to 14; as table 2 shows, the number of samples used for the
2001 draft is greater. In addition, while EPA recognized that PCBs
were being identified in foods, the agency did not have sufficient
data at that time to develop estimates of the levels of specific PCBs
in foods; the 2001 draft does include estimates of PCB levels in foods.
The following sections describe in greater detail the samples EPA used
to identify the level of dioxins in 9 of the 10 foods studied”beef,
pork, and poultry; freshwater and marine fish; milk, dairy, and eggs;
and vegetable fat”and any associated limitations or uncertainties.
(The draft reassessment report does not provide any information
supporting EPA's estimate of the types and amounts of dioxins in other
meats, the tenth food type.[Footnote 12] In commenting on a draft of
our report, EPA said that information on other meats would be provided
in its final report.)
Beef, Pork, and Poultry:
In estimating exposure to dioxins from beef, pork, and poultry, EPA
used data from the first statistically designed national surveys of
dioxin levels in these foods sponsored by EPA and USDA. These surveys
were designed to be representative of all U.S. regions and all classes
of animals slaughtered in federally inspected slaughtering
establishments. EPA believes the three surveys provide reasonable
estimates of the average national concentrations of dioxins in beef,
pork, and poultry. Nonetheless, information EPA provided in the draft
reassessment report about these samples identifies some limitations
and uncertainties about these studies.
* The samples are now between 6 and 8 years old and therefore may not
reflect current exposures. To address this data gap, EPA and USDA are
conducting a follow-up study on dioxin levels in beef, pork, and
poultry that will commence in 2002 and provide updated information.
However, EPA officials said the results of this survey will likely not
be available for incorporation into the dioxin reassessment report
that EPA plans to publish this year.
* The animal samples for beef, pork, and poultry were not meat
products sold in grocery stores but rather were cuts of fat generally
not consumed”either back fat, abdominal fat, or belly fat from
slaughtering establishments. Some uncertainty therefore surrounds the
accuracy of EPA's estimates of dietary intake of dioxins because of
comparability concerns. EPA used this approach because USDA federal
inspectors could obtain the samples with little disruption to the
slaughtering establishments and because the samples' high fat content
would enable more accurate measurement of dioxins, since the analysis
would be of highly concentrated fat samples. However, this approach
assumes that edible meat products sold in grocery stores contain the
same types and amounts of dioxins as the fat samples (adjusted for
differences in percentages of fat). According to EPA, this assumption
is supported by a well-developed understanding of the manner in which
dioxins distribute across fat reservoirs in vertebrates. Therefore,
EPA concluded that the fat samples for all three foods were comparable
to the edible meat samples. EPA also based its conclusion on its
analysis of beef samples”comparing five back fat samples with other
cattle parts, including muscle tissue, which could be representative
of edible beef products.[Footnote 13] For the five samples, the ratios
of CDDs and CDFs in muscle fat to CDDs and CDFs in back fat varied by
up to 300 percent, ranging from 0.58 to 1.7; and the ratios for PCBs
varied by up to 50 percent, from 1.0 to 1.5.[Footnote 14] Although
some of the variation may result from imprecision inherent in
measuring picograms, this limited analysis indicates that using fat
samples may overstate or understate to some extent the dioxin levels
in beef, pork, and poultry products.
* EPA reported that it excluded 2 of the 80 samples of abdominal fat
from poultry because they had significantly higher concentrations of
certain dioxins than the other samples. EPA, USDA, and the Food and
Drug Administration investigated the cause of these elevated dioxin
levels and determined that it stemmed from contaminated animal feed
that had been distributed to poultry, fish, hog, and cattle producers
in several southern and southwestern states!' EPA considered the two
poultry fat samples inappropriate for the dioxins study, which was
aimed at identifying typical exposures to dioxins. However, it is not
clear that the poultry samples with high concentrations of dioxins
were anomalies because the incidence of dioxin contamination in animal
feeds is not known. For example, this instance of contaminated animal
feed was discovered by the first national poultry sample, which tested
only 80 samples nationwide.
* In response to suggestions from a peer review panel, when the data
were sufficient to do so, EPA presented a standard deviation”the
typical amount of variability around the mean”on its estimates of the
average levels of dioxins in the foods, as well as the range of the
levels of dioxins identified in the samples. For beef, pork, and
poultry, EPA was able to provide this information for the CDDs and
CDFs. These data indicated considerable variability in the levels of
CDDs and CDFs in the foods. For example, the estimated level of 0.28
picograms of dioxins in a gram of pork has a standard deviation of
plus or minus 0.28. In other words, the standard deviation is equal to
or greater than the mean. Accordingly, the estimated dioxin level is
subject to a wide range of uncertainty.
* Because EPA did not have sufficient information to develop a
standard deviation for PCBs, the agency could not develop a standard
deviation for total dioxins (the combination of CDDs, CDFs, PCBs) in
beef, pork, and poultry. As a result, EPA could not state with any
degree of certainty that exposure to total dioxins or to PCBs would
fall within specified levels. EPA believes this limitation is a minor
one because it considers the average exposure level, rather than the
more limited extreme exposures, to be of greater public health
interest. Nonetheless, this additional analysis, if available, would
enable policymakers, scientific peer reviewers, and other users to
better evaluate the extent to which the data may be representative of
average national exposures.
Freshwater and Marine Fish and Shellfish:
Though EPA analyzed more fish samples for the current reassessment
draft than for earlier drafts, the current draft report acknowledges
that the levels of dioxins in fish are more uncertain than those in
the other foods for two reasons. First, the data lack the "geographic
coverage and statistical power" of the other food surveys. That is,
while the sample sizes for CDDs and CDFs in fish are considerably
larger than those used for the analyses of other foods, they do not
provide data that are nationally representative because of the
diversity of fish and bodies of water. Specifically, there are a
significant number and variety of freshwater and marine fish species
living in numerous bodies of water that contain differing types and
levels of dioxins. Moreover, fish consumed in the United States
include both farm-raised and wild fish. Second, EPA based its
estimates for levels of PCBs in fish on a much smaller data set than
it used for CDDs and CDFs. EPA used 222 samples to estimate the levels
of CDDs and CDFs in freshwater fish and shellfish and 158 samples for
marine fish and shellfish compared with 7 and 6 composite samples for
PCBs for freshwater and marine fish, respectively. Further, most of the
samples for PCBs were from Canadian rather than U.S. cities, and the
analyses of levels of PCBs in them did not evaluate all of the PCBs
identified as being toxic. For example, according to the report, only
one of the composite samples for marine fish and shellfish, collected
between 1984 and 1986, was analyzed for the presence of the most
common and toxic PCB, referred to as PCB-126. For these reasons, EPA
acknowledges in the draft report that the resulting estimates are not
representative of the level of dioxins in fish nationally. We note
that the limitations of the data used to estimate the levels of PCBs
in fish are particularly significant because in the report, EPA
estimates that freshwater fish contains the highest levels of PCBs
(and total dioxins) of all the foods studied.
The samples EPA used to estimate the levels of dioxins in fish were
derived from EPA's National Bioaccumulation Study[Footnote 16] and
three market basket surveys in the United States and Canada. Samples
for the bioaccumulation study were collected between 1986 and 1989,
whereas the samples for the market basket surveys were collected about
a decade later, between 1995 and 1999. Some of the limitations and
uncertainties associated with these samples that EPA acknowledged in
the draft report are highlighted below.
* Most of the fish samples used for the reassessment draft were
collected 5 or more years ago; some are between 13 and 16 years old.
* EPA did not have sufficient data to estimate exposure to PCBs from
eating freshwater or marine shellfish.
* Some of the estimates for freshwater fish, such as trout, are based
on samples from the bioaccumulation study that may be more
representative of wild fish (i.e., fish caught in recreational
fishing) than fish typically purchased by the general population at
grocery stores, which is largely farm-raised. Specifically, in cases
in which EPA did not have data on farm-raised freshwater fish or fish
purchased in grocery stores, the agency used the concentration of CDDs
and CDFs from samples of wild caught fish from the bioaccumulation
study. This use of older data on wild fish increases the uncertainty
about the representativeness of EPA's exposure estimate.
* For some fish species, such as mullet and mackerel, estimates were
based entirely on samples collected in the Mississippi area and
therefore may not be representative of levels seen in other locations.
* EPA did not have sufficient data to estimate a standard deviation
for the average levels of dioxins in freshwater or marine fish. As a
result, EPA cannot state with any degree of certainty what the related
dietary exposure to dioxins is.
Milk, Dairy, and Eggs:
The milk samples upon which both the milk and dairy estimates are
based came from a national survey. In this survey, samples were
collected during the four seasons, providing information on seasonal
(temporal) variations. The milk samples were collected from 51
sampling stations, located in a majority of the states, that support
EPA's Environmental Radiation Ambient Monitoring System.[Footnote 17]
In contrast, the estimates for CDDs and CDFs in eggs are based on Food
and Drug Administration market basket surveys in 1997 in California,
Georgia, Minnesota, New York, Ohio, Oregon, Pennsylvania, and
Wisconsin. The estimates for PCBs in eggs are based on market basket
surveys in San Diego, California; Atlanta, Georgia; Binghamton, New
York; and five major Canadian cities. EPA used composite samples of
milk and eggs to identify and measure the presence of specific dioxins
in milk, dairy, and eggs. Information provided in the draft report
identifies some limitations associated with these data.
* Most of the milk samples were collected 6 years ago.
* The egg samples used to support the analyses for CDDs and CDFs were
collected 5 or more years ago. The estimates for PCBs in eggs are
based, in part, on samples obtained in five Canadian cities between 14
and 16 years ago.
* Only one of the six composite samples used to estimate the level of
PCBs in eggs was analyzed for the presence of the most common and
toxic PCB.
Vegetable Fat:
According to EPA, its estimates of CDDs and CDFs in vegetable fat were
developed from a market basket survey that was not representative of
edible oil consumption in the United States. The 30 samples of various
oils, solid shortening, margarine, and an oil spray were obtained from
grocery stores in nine U.S. cities or metropolitan areas: Chicago,
Illinois; Cincinnati, Ohio; Denver, Colorado; Miami, Florida;
Minneapolis, Minnesota; Salt Lake City, Utah; San Antonio, Texas; San
Francisco, California; and the Washington, D.C., metropolitan area.
Although neither the reassessment report nor the study (published in
1996) states when the samples were collected, there is typically at
least a 1-year lag between collection and publication, indicating that
the samples were collected 8 or more years ago. EPA used limited data
to estimate the level of PCBs in vegetable fat. This estimate is
derived from five composite samples of cooking fats and salad oils,
each of which was obtained 14 or more years ago from one of five major
(unidentified) Canadian cities. As a result of these limitations that
EPA identified in the draft report, the estimate for dietary exposure
to dioxins from eating vegetable fats is unlikely to reflect current
average dietary exposure in the United States.
Method EPA Used to Estimate Toxicity of Dioxins in the 10 Food Types
Is Accepted by Experts but Has Limitations:
After using the chemical analyses discussed previously to identify the
types and quantities of dioxins present, EPA estimated the toxicity of
the dioxins in the 10 types of foods, using measures called toxic
equivalency factors. (As noted earlier, these measures”called TEFs”are
used to create a frame of reference by comparing the potential
toxicity of individual dioxins in a sample with the toxicity of the
most toxic and best understood dioxin, TCDD, which is assigned a TEF
of 1.) EPA used the TEFs that were updated by WHO in 1997. For each of
the types of foods, EPA multiplied the measured types and amounts of
the dioxins present by the related TEFs to arrive at a "dioxin toxic
equivalence value" for that particular food category/dioxin
combination.[Footnote 18] For each food category, the total dioxin
toxic equivalency is the sum of these products”that is, the sum of the
toxic equivalence values for (1) CDDs and CDFs and (2) PCBs. This
provides an indicator of the relative toxic concentration of dioxins
in each food category. As table 4 shows, EPA estimated that freshwater
fish and shellfish had the largest per-gram concentration of dioxins
with toxic effects.
Table 4: EPA's Estimates of Toxic Concentrations of Dioxins in 10 Food
Categories, Picograms per Gram:
Food category: Freshwater fish and shellfish;
Dioxin toxic equivalence values for CDDs and CDFs: 1.00;
Dioxin toxic equivalence values for PCBs: 1.20;
Total dioxin equivalence values: 2.20.
Food category: Marine fish and shellfish;
Dioxin toxic equivalence values for CDDs and CDFs: 0.26;
Dioxin toxic equivalence values for PCBs: 0.25;
Total dioxin equivalence values: 0.51.
Food category: Pork;
Dioxin toxic equivalence values for CDDs and CDFs: 0.28;
Dioxin toxic equivalence values for PCBs: 0.01;
Total dioxin equivalence values: 0.29.
Food category: Beef;
Dioxin toxic equivalence values for CDDs and CDFs: 0.18;
Dioxin toxic equivalence values for PCBs: 0.08;
Total dioxin equivalence values: 0.26.
Food category: Other meats;
Dioxin toxic equivalence values for CDDs and CDFs: 0.18;
Dioxin toxic equivalence values for PCBs: 0.04;
Total dioxin equivalence values: 0.22.
Food category: Eggs;
Dioxin toxic equivalence values for CDDs and CDFs: 0.08;
Dioxin toxic equivalence values for PCBs: 0.10;
Total dioxin equivalence values: 0.18.
Food category: Dairy;
Dioxin toxic equivalence values for CDDs and CDFs: 0.12;
Dioxin toxic equivalence values for PCBs: 0.06;
Total dioxin equivalence values: 0.18.
Food category: Poultry;
Dioxin toxic equivalence values for CDDs and CDFs: 0.07;
Dioxin toxic equivalence values for PCBs: 0.03;
Total dioxin equivalence values: 0.10.
Food category: Vegetable fats;
Dioxin toxic equivalence values for CDDs and CDFs: 0.06;
Dioxin toxic equivalence values for PCBs: 0.04;
Total dioxin equivalence values: 0.10.
Food category: Milk;
Dioxin toxic equivalence values for CDDs and CDFs: 0.02;
Dioxin toxic equivalence values for PCBs: 0.01;
Total dioxin equivalence values: 0.03.
Note: The toxic equivalence values are estimated on a whole (wet)
weight basis, as opposed to a dry weight basis.
Source: Derived from U.S. EPA, October 2001 draft dioxin reassessment
report.
[End of table]
The toxic equivalence approach using TEFs has evolved over the last 20
years and is the internationally accepted scientific approach for risk
assessments of dioxins. This approach has been formally adopted by
several countries and as guidance by international organizations, such
as WHO. TEFs are used to decrease the overall uncertainty in assessing
the health risks of dioxins because they provide a framework for
addressing the complex mixtures of dioxins to which people are most
often exposed. Nonetheless, a number of uncertainties are involved in
the use of the TEF concept. As a result of these uncertainties,
estimates of the concentrations of dioxins in foods based on this
approach may be overstated or understated.
The draft reassessment report acknowledges that there are still many
questions about the use of the TEF method and the validity of some of
the underlying assumptions. The report states that many assumptions
are necessary because of lack of data. Specifically, the derivation of
TEFs is limited by the amount of available data on the relative
potency of different dioxins compared with TCDD. For many dioxins, the
available data on relative potency may be limited to only a few
experimentally observed effects. Some of these effects may not be
considered toxic by themselves, but they still might provide evidence
that exposure to dioxins led to biological or chemical effects in
experimental subjects. For example, EPA noted that only TCDD and one
mixture of certain dioxins have been tested for carcinogenicity.
Therefore, in order to develop a TEF that estimates the cancer potency
of a mixture including other dioxins, scientists have assumed that the
relative potencies observed for noncancer effects approximate those
for cancer. In other words, once derived, TEFs apply to all effects,
not just those for which relative potency data were available.
Nonetheless, after considering a number of the uncertainties and
limitations of this approach, the international experts who derived
the current TEFs concluded that the TEF concept is still the most
plausible and feasible approach for risk assessment of dioxins.
Furthermore, the TEF values for individual dioxins are reevaluated and
updated periodically to reflect the available evidence. When WHO
established the most recent TEFs in 1998, it suggested that the toxic
equivalency scheme be reevaluated every 5 years and that the TEFs and
their application to risk assessment be reanalyzed to account for
emerging scientific information.
Daily Dietary Intake Estimates Are Primarily Based on Food Surveys of
U.S. Adults Administered Between 1989 and 1991:
To develop its estimate of the daily dietary intake of dioxins by the
average adult in the United States, EPA needed to calculate the amount
of food containing dioxins that Americans typically eat. EPA obtained
this information for the 10 food types from USDA food intake surveys.
The USDA survey data include information on the amounts of specific
foods consumed in a day by an average person weighing 70 kilograms
(154 pounds).
USDA obtained its data from detailed food surveys prepared by
thousands of individuals selected from statistical samples. In these
surveys, individuals generally provided detailed information on food
consumption for 2 days. The surveys used statistical sampling to
ensure that all seasons, geographic regions of the United States, and
demographic and sociodemographic groups were represented. EPA's
analysis of these data tabulated intake rates for the major foods, as
well as for individual food items. The total quantity of each food
eaten by the survey population in a survey day was tabulated and
weighted to represent the quantity eaten by the entire U.S. population
in a typical day. For the draft reassessment report, EPA averaged
USDA's data for three age groups of adults ranging from ages 20 to 70
and over. Table 5 provides EPA's estimates of the daily dietary intake
of 10 food types by adults in the United States.
Table 5: Estimated Daily Dietary Intake of 10 Food Types for an
American Adult Weighing 70 Kilograms (154 pounds):
Food: Milk;
Estimated dietary intake (grams per day): 175.0.
Food: Dairy;
Estimated dietary intake (grams per day): 55.0.
Food: Beef;
Estimated dietary intake (grams per day): 50.0.
Food: Poultry;
Estimated dietary intake (grams per day): 35.0.
Food: Other meats;
Estimated dietary intake (grams per day): 25.0.
Food: Eggs;
Estimated dietary intake (grams per day): 17.0.
Food: Vegetable fats;
Estimated dietary intake (grams per day): 17.0.
Food: Pork;
Estimated dietary intake (grams per day): 1.5.
Food: Marine fish and shell fish;
Estimated dietary intake (grams per day): 9.6.
Food: Freshwater fish and shellfish;
Estimated dietary intake (grams per day): 5.9.
Source: Derived from U.S. EPA, October 2001 draft dioxin reassessment
report.
[End of table]
While EPA prefers to use USDA food data from the 1989-91 USDA
Continuing Survey of Food Intake By Individuals because it has
conducted a statistical analysis of these data and includes them in
the agency's Exposure Factors Handbook,[Footnote 19] the draft
reassessment report uses other data for fish and does not provide
information on the basis for its estimates of dietary intake of other
meats. Specifically, the draft reassessment report derived its
estimates of the daily dietary intake of beef, pork, poultry, milk,
dairy products, vegetable fats, and eggs from USDA's Continuing Survey
Food Intake By Individuals conducted from 1989 through 1991. In
contrast, the daily dietary intake of freshwater and marine fish and
shellfish were derived from a March 2000 report on the consumption of
fish prepared by EPA's Office of Water. This report used data from
USDA's Continuing Survey of Food Intakes By Individuals conducted in
1994, 1995, and 1996. In this report, EPA weighted its estimates of
exposure to dioxins from fish by the species-specific concentrations
according to species-specific fish consumption rates for the U.S.
population. However, in cases where species-specific concentration
data were not available, EPA used default values. For example, EPA
used data from the bioaccumulation study as the default for certain
freshwater fish. The use of various default assumptions adds
uncertainty to the exposure estimates.
EPA officials said that EPA did not use more current dietary intake
data from USDA in the October 2001 draft reassessment because EPA has
not yet fully reviewed surveys subsequent to the 1989-91 surveys that
it uses in its Exposure Factors Handbook. EPA officials told us that
they did not believe it was necessary to use more current data because
the dietary habits of Americans have changed very little over the
course of the past decade. These officials cited data collected in
surveys conducted between 1994 and 1996 that show little change in the
intake of the 10 foods compared with surveys conducted between 1989
and 1991.
EPA's and WHO's Specific Reassessment Objectives and Processes
Differed, but Their Analytical Methods and Conclusions on Dioxins'
Health Risks Are Similar:
EPA and WHO have undertaken extensive efforts to reassess the health
risks of exposure to dioxins. EPA's comprehensive dioxin reassessment
objective has been to characterize the potential human health risks
posed by exposure to dioxins. To do this, EPA used an extensive,
multiyear review process. In contrast, WHO had more narrowly focused
primary objectives and conducted its reassessments of dioxins through
a succession of individual reviews and meetings. Nonetheless, EPA and
WHO used very similar analytical methods to identify the types of
potential human health hazards associated with exposure to dioxins and
assess the probability and severity of harm given different levels of
exposure. Moreover, the conclusions EPA and WHO reached on the basis
of their respective reassessments also reflected much agreement.
However, there were some significant issues on which EPA and WHO
differed, such as whether there are threshold doses of dioxins to
which humans could be exposed over a lifetime without significant risk
of cancer and whether dioxins other than TCDD are human carcinogens.
EPA Undertook a Comprehensive Assessment, While WHO Used a Succession
of Individual Reviews and Meetings:
In general, both EPA and WHO focused their evaluations of the health
effects and risks associated with dioxins on TCDD and 28 other related
chemical compounds (including 12 dioxin-like PCBs) for which consensus
toxic equivalency factors had been established through a 1997 meeting
organized by WHO.[Footnote 20] However, there were important
differences in some of the specific objectives of EPA's and WHO's
dioxin reassessments and the processes used by EPA and WHO to develop
the reassessments.
EPA's overall objective has been very broad: to characterize the
available scientific information on the potential health risks posed
by exposures to dioxins. EPA therefore addressed each of the four
major components of a chemical risk assessment: hazard identification,
dose-response assessment, exposure assessment, and risk
characterization.[Footnote 21] The resulting characterization of risks
posed by dioxins can be used to inform risk management decisions, such
as whether and where to set or revise regulatory standards, but other
information and factors would also enter into such decisions.[Footnote
22] The process by which EPA has undertaken this task has been a
comprehensive, multiyear review. Moreover, the EPA reassessment has
included multiple independent scientific peer reviews of various draft
reports by EPA's Science Advisory Board and others. EPA has also
solicited public review and comments on its draft reassessment.
WHO's reassessment objective also addressed a broad range of data and
issues regarding the potential exposures and health risks associated
with dioxins, but the specific reports and evaluations WHO produced on
dioxins generally had more narrowly focused primary objectives than
EPA's reassessment report. In addition, rather than a comprehensive,
integrated process such as EPA's, WHO's process consisted of
individual evaluations and meetings for each of those particular
objectives.[Footnote 23]
* In 1997, the International Agency for Research on Cancer (IARC), a
chief contributor to WHO's dioxin risk assessments, published
monographs covering TCDD and 16 other dioxins. (This agency publishes
the results of its evaluations of specific chemicals in its series
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. In
the rest of this report, we call the monographs covering TCDD and
other dioxins the 1997 cancer monographs.) The primary objective
leading to these monographs was to classify TCDD and other specific
dioxins under a standard scheme that identifies whether and under what
circumstances substances are human carcinogens.[Footnote 24]
Essentially, this objective corresponds to the hazard identification
step of EPA's four-step risk assessment process.
* Under its activities related to the European Centre for Environment
and Health, WHO organized two meetings of experts addressing issues on
the health effects of dioxins. In June 1997, WHO convened experts in
Stockholm, Sweden, to derive consensus toxic equivalency factors for
29 dioxins that could be used for human, fish, and wildlife risk
assessments. In May 1998, WHO convened 40 experts from 15 countries in
Geneva, Switzerland, to evaluate scientific data on the health risks
and exposures of dioxins with the principal objective of updating the
estimated amount of dioxins to which humans can be exposed daily
without appreciable harm. In the rest of this report, we call these
efforts, respectively, the 1997 TEF meeting and the 1998 consultation.
* At the 57th meeting of the Food and Agriculture Organization of the
United Nations/WHO Joint Expert Committee on Food Additives in June
2001 in Rome, Italy, the committee for the first time evaluated the
risks associated with the presence of dioxins in food. The
participants specifically evaluated dioxins (among other specific food
additives and contaminants), with the view toward recommending
acceptable intakes for dioxins contained in foods. The committee used
the 1998 consultation's assessment as the starting point for its
evaluation but took into account newer studies. In the rest of this
report, we call this evaluation the 2001 food additives meeting.
Appendix I highlights some of the major milestones in the EPA and WHO
assessments of dioxin risks, with a particular focus on the
reassessment efforts that both entities began in the 1990s.
EPA and WHO Used Similar Analytical Methods:
Despite differences in some of the specific objectives and processes
of their respective reassessment efforts, EPA and WHO used similar
analytical methods to identify and assess the potential health risks
of dioxins. Through these analyses, EPA and WHO identified the types
of potential hazards that might be associated with exposure to
dioxins, the circumstances under which these substances could cause
adverse effects, and the probability and severity of expected effects
given different levels of exposure to dioxins. Specifically, both EPA
and WHO:
* reviewed available scientific data from many studies of humans and
animals covering a variety of effects potentially associated with
exposure to dioxins;
* continued to consider cancer risks, as in the original dioxin risk
assessments, but also paid increasing attention to noncancer health
effects, such as changes in reproductive and developmental functions
and the immune and nervous systems, as well as other health problems,
such as chloracne (a chronic and disfiguring skin disease) and
alterations in liver enzyme levels;
* reviewed evidence regarding other biochemical, molecular, or
cellular effects that have been observed in various studies, agreeing
that these effects might be precursors to subsequent adverse effects;
and;
* considered a range of analytical methods, models, and approaches to
assess the dose-response relationships for exposure to dioxins.
EPA and WHO also used some analytical concepts and methods that they
agreed were more appropriate to the analysis of dioxins than those
that are often used for risk assessments of other chemicals. For
example, both entities used body burden”the concentration of dioxins
in the body”instead of other dose measures, such as daily intake, to
compare risks between humans and animals and determine doses that
would be of equivalent risk in humans and animals. The organizations
also concurred that the concept of toxic equivalency should be used to
facilitate risk assessment of dioxins and complex mixtures of dioxins.
Furthermore, in contrast to chemical risk assessments in general, EPA
and WHO often had sufficient data to focus on the dose level
associated with a 1-percent increase in a particular effect (rather
than being limited to the level associated with a 10-percent increase)
and seldom had to extrapolate outside the observed doses or exposures
from the studies that they used to prepare the reassessments.
Much of the scientific data available to EPA and WHO on the potential
effects of exposure to dioxins came from animal studies, mainly
studies of TCDD on a variety of species. (According to WHO, most other
dioxins and dioxin-like compounds are "relatively poorly studied"
compared with TCDD.[Footnote 25]) However, EPA's and WHO's recent
reassessment efforts also benefited from the increasing quantity and
quality of data on the effects of dioxins in humans that became
available during their reassessments. Among the sources of these human
data were studies of occupational exposure of people who produce and
apply herbicides; residents in a contaminated area of Seveso, Italy
(where an accident at a chemical factory had released a cloud of toxic
chemicals, including dioxins, in 1976); and noncancer effects in
infants and children.
EPA and WHO Had Similar Overall Conclusions but Differed on Some
Important Issues:
The conclusions EPA and WHO reached on the basis of their respective
dioxin reassessments were frequently similar, but some significant
differences also emerged. With respect to the major areas of
agreement, both EPA and WHO concluded that TCDD is a human carcinogen
and that:
* dioxins can cause a variety of both cancer and noncancer health
effects,
* dioxins act in the same way within the body to cause the effects
observed in animals and humans,
* dioxins adversely affect human health at lower exposure levels than
previously thought, and,
* some effects could occur at or near the levels to which the general
population is now being exposed.
EPA and WHO not only concurred at the broad level of these conclusions
but also on many of the supporting details. For example, both entities
had similar reasons for concluding that TCDD is a human carcinogen:
the combination of sufficient evidence that TCDD causes cancer in
animals, more limited evidence of carcinogenicity from human data, and
strong evidence that TCDD operates through the same mode, or
mechanism, of action in animals and humans.[Footnote 26]
The major differences of opinion between EPA and WHO concerned whether
(1) there is a threshold below which exposure to dioxins would not be
expected to cause cancer, (2) it is useful to calculate a "tolerable"
dose of dioxins or estimate a dose without appreciable risk of
deleterious effects to which humans can be exposed over a lifetime,
and (3) both mixtures of dioxins and dioxins other than TCDD are
likely human carcinogens. In addition, EPA quantified the general
population's possible additional risk of developing cancer from
exposure to dioxins, while WHO did not. Such differences may make it
more difficult for interested parties to compare the results of EPA
and WHO dioxin risk assessments. The following sections provide
additional information on each of these differences.
Cancer Threshold:
EPA and WHO disagreed about whether there is a threshold below which
exposure to dioxins would not cause cancer. EPA concluded that
available evidence was insufficient for the agency to depart from its
default linear cancer risk assessment approach, which is based on an
assumption that no threshold exists regarding adverse effects (i.e.,
any exposure to carcinogenic substances, no matter how small, poses
some risk of developing cancer).[Footnote 27] In contrast, WHO
concluded that there is a threshold for all adverse effects, including
cancer. Specifically, WHO concluded that dioxins do not initiate
cancer through a direct effect on genetic material (that is, they are
non-genotoxic carcinogens) and, therefore, do not warrant a linear (no
threshold) assessment of risk. WHO also concluded that noncancer
health effects occurred at lower body burdens (concentrations) of
dioxins than the body burdens at which cancer occurred in animals.
Accordingly, WHO determined that establishing a tolerable intake based
on estimated thresholds for noncancer effects would also address any
cancer risks (that is, if the intake were set to avoid appreciable
noncancer health consequences, it should also avoid appreciable
consequences concerning cancer).
Estimating a "Tolerable" Dose or One Without Appreciable Risk:
WHO programs estimated a tolerable daily intake for dioxins in 1998
and a tolerable monthly intake in 2001. These measures represent the
amounts of dioxins that the WHO experts believe a human could ingest
daily or monthly for a lifetime without appreciable health
consequences. Expressing these estimates as "tolerable" intakes
generally does not connote that such intakes are acceptable or risk
free, but rather that any health consequences would be judged to be
tolerable while exposure is continuing to be reduced.[Footnote 28]
EPA's related (but not identical) measure is the reference dose, which
would estimate a daily exposure to the human population, including
sensitive subgroups, that is likely to be without an appreciable risk
of deleterious effects during a lifetime.[Footnote 29] EPA, however,
chose not to calculate a reference dose for dioxins, as it generally
does for noncancer health assessments of other substances. According
to EPA, it did not do so because any reference dose that it would
recommend for dioxins would likely be below (perhaps considerably
below) the current background intake levels and body burdens of the
U.S. population. EPA pointed out that reference doses are typically
calculated to address the risks of incremental exposures over
background exposure.[Footnote 30] In the case of dioxins, however,
background exposure is a significant component of total exposure.
Therefore, in EPA's opinion, a reference dose would be uninformative
to risk managers for safety assessment. EPA also noted that, if it
were to set a reference dose, its estimate likely would be more
stringent than the tolerable intake levels for dioxins proposed by WHO
because EPA's traditional approach for setting a reference dose gives
more weight to scientific uncertainties than the approach WHO used in
setting its tolerable intake level.
EPA chose instead to use an alternative approach, the margin of
exposure, to characterize noncancer risks. The margin of exposure is a
ratio that shows how far the actual (or estimated) total human
exposure to a particular substance is from levels at which adverse
effects have been demonstrated to occur in human or animal studies.
The margin of exposure is an alternative way of characterizing the
likelihood that noncancer effects may be occurring in the human
population at environmental exposure levels. A reference dose, on the
other hand, estimates a level of exposure below which EPA considers it
unlikely that any adverse effects will occur. EPA generally considers
margins of exposure of 100 or more as adequate to rule out the
likelihood of significant effects occurring in humans. However, for
the most sensitive effects identified with dioxins (i.e., those that
occurred at the lowest doses of exposure), the margins of exposure
ranged from 15 to less than 1.
Characterizing Cancer Risks Posed by TCDD, Other Individual Dioxins,
and Mixtures of Dioxins:
EPA and WHO both characterize TCDD as carcinogenic to humans. While
EPA further characterizes other individual dioxins and mixtures of
dioxins as "likely to be human carcinogens," WHO does not.
Specifically, WHO states that the carcinogenicity of dioxins other
than TCDD cannot be determined because of insufficient data. This
difference of opinion largely reflects the specific objectives and
scopes of EPA's and WHO's assessments. EPA's conclusion reflects a
"weight of the evidence" judgment”that is, it is based on EPA's entire
reassessment of dioxins (resting, in particular, on the conclusion
that all dioxins share a similar mode of action and using evidence
from both animal and human studies). In contrast, WHO's cancer
monographs looked only at individual dioxins, focusing on whether they
met specific criteria. Consequently, WHO's conclusions reflected a
narrower data set and did not address the risks posed by mixtures of
dioxins. However, because most human exposure is to mixtures rather
than individual dioxins, and both EPA and WHO advocate using the same
toxic equivalency factors for assessing the dioxins in such mixtures,
any differences in the carcinogenicity classifications may have little
practical impact.
Quantifying Cancer Risks:
Quantifying the lifetime cancer risk to the general population from
exposure to dioxins was an important component of EPA's dioxin
reassessment. EPA estimated that the upper bound on the general
population's lifetime risk for all cancers from dioxins might be on
the order of 1 in 1,000 or more (i.e., people might experience a 1 in
1,000 increased chance of developing cancer over their lifetime
because of exposure to dioxins). EPA's reassessment also states that
the vast majority of the population is expected to have less risk per
unit of exposure and some may have zero risk. WHO did not carry out
such a quantitative assessment of the general population's cancer risk
for two main reasons. First, calculations of population risk are
beyond the scope of WHO's IARC cancer monographs, which evaluate
whether and under what circumstances particular substances could pose
a cancer risk to humans but generally do not provide quantitative risk
estimates.[Footnote 31] Second, as noted previously, WHO's conclusion
about a cancer threshold for dioxins led it to focus on noncancer
effects when deriving tolerable intake levels for dioxins. However,
WHO did explore the calculation, through modeling, of a cancer
"benchmark dose," the dose or body burden estimated to result in a 1-
percent increase in cancer mortality. But WHO noted that its estimates
for this benchmark dose ranged quite widely and strongly depended on
the assumptions made during the modeling.
Appendix II provides a more detailed comparison of the EPA and WHO
conclusions regarding a number of major issues covered by the
entities' dioxin risk assessments.
EPA's Draft Dioxin Reassessment Report Generally Reflects the Views of
Recent Peer Reviews:
Two independent peer review panels, including an EPA Science Advisory
Board[Footnote 32] panel, reviewed major sections of EPA's draft
dioxin reassessment report in 2000. Both panels generally agreed with
a number of key assumptions and approaches that EPA used to develop
its updated health risk assessment of dioxins. Each of the peer review
panels had a number of recommendations and suggestions for EPA to
address or consider, most of which focused on the approaches and
methodologies used to depict the health risks associated with dioxins.
EPA made a number of revisions to its draft report in response to
these recommendations and comments. The peer review panels disagreed
with EPA on a few major points, and the Science Advisory Board panel
emphasized the need for additional research to bridge gaps in data.
Two Peer Review Panels Reviewed the Draft Dioxin Reassessment Report
in 2000 and Concurred on Many Key Aspects:
Both an independent expert peer review panel and one convened by EPA's
Science Advisory Board reviewed the draft reassessment report on
dioxins in 2000. These reviews resulted in part from the Board's
review of an earlier version of EPA's draft reassessment report. In
1995, a Board panel had reviewed the draft reassessment and requested
that EPA make substantive revisions to the chapter on dose-response
modeling[Footnote 33] and to the Integrated Summary. The Board had
also requested that EPA develop a separate chapter on toxicity
equivalence factors and submit the revised dose-response and new
toxicity chapters to external peer review before the next Board review
of these sections. In response, EPA revised the chapter on dose-
response modeling and had it peer reviewed in 1997. Similarly, EPA
wrote a chapter on toxicity equivalence factors and had it peer
reviewed as part of the July 2000 review.
July 2000 External Peer Review Panel:
In July 2000, EPA organized an independent peer review panel to review
the revised Integrated Summary and the new chapter on toxicity
equivalence factors. To obtain an objective critique, EPA had a
contractor select 12 independent individuals with expertise in several
technical fields, including risk characterization and communication;
toxicology; epidemiology; sources of, and population exposure to,
dioxins and related compounds; mechanisms and mode of action; and
toxic equivalency. The panel addressed 20 questions about the
reassessment report regarding exposure to and the health risks of
dioxins. Table I of appendix III lists the questions the July 2000
panel addressed in its review.
The panel generally agreed with the approaches and methodologies EPA
used in its reassessment, and noted, among other things, the following:
* Body burden”the concentration of dioxins in the body”is an
appropriate "dose metric" (measure) for comparing health risks across
species.
* The use of margin of exposure”a ratio that shows how far actual or
estimated human exposure is from levels at which adverse effects have
been demonstrated to occur in human or animal studies” is a more
logical approach to characterizing noncancer risk of dioxins than
comparing exposure to a reference dose.
* The report's information on noncancer effects in animals and humans
was adequately assembled, and the explanation of why dioxins' effects
observed in animals are of concern to humans was also sufficient.
* The history, rationale, and support for the toxicity equivalence
approach, which is used to assess risks posed by dioxins and complex
mixtures of dioxins on the basis of their toxicity relative to an
equivalent dose of TCDD, were adequately presented.
As discussed further below, the July 2000 panel also provided several
recommendations and suggestions and identified the topics of greatest
concern for finalizing the Integrated Summary.
The Board Panel:
Once the July 2000 panel published its recommendations and suggestions
in August 2000, EPA addressed them and sent its revised draft to the
Science Advisory Board's dioxin reassessment review subcommittee panel
in September 2000. The panel comprised several professors and
directors employed by medical institutions and representatives of
industry-affiliated research organizations, consulting firms, and
state health agencies. The Board panel met to review the revised
sections of the draft reassessment report in November 2000. The Board
agreed to answer 20 questions on the reassessment report regarding
exposure to and the health risks of dioxins. Most of these questions
were similar to those asked of the July 2000 panel. The Board panel
completed its review and published a report in May 2001. Table 2 of
appendix III lists the questions the Board panel addressed in its
review.
The Board panel, as the July 2000 panel before it, endorsed several
key aspects of the reassessment, noting that, among other things, EPA
had:
* used appropriate dose metrics, such as body burden, to equate risks
across species;
* assembled and distilled a large and diverse body of literature on
noncancer effects into a coherent document;
* properly chosen the margin-of-exposure approach to characterize
noncancer risks;
* used toxicity equivalence factors to effectively address the joint
effects of complex mixtures of dioxins on human health; and;
* compiled an outstanding inventory of dioxin sources and effectively
characterized the estimates of background exposure to dioxins using
the available scientific data.
The Board panel stated that, overall, EPA had prepared a thorough and
objective summarization of the data and had addressed the key issues
the Board had set forth in its 1995 review of the draft. The Board
panel concluded that there was no need to submit further revisions of
the reassessment report and that EPA should proceed to complete and
release the document. However, as discussed in the following section,
the Board panel provided several recommendations and suggestions for
EPA to improve the draft document before its release. The Board panel
also recognized the need for additional research to bridge gaps in
data that limit EPA's ability to determine the magnitude of the health
risks associated with dioxins. In essence, the Board panel viewed this
reassessment as an interim assessment, recognizing that the data gaps
are not likely to be addressed in the foreseeable future.
EPA's Draft Reassessment Report Reflects Changes Made in Response to
Recommendations and Suggestions of Peer Reviews:
While the peer review panels generally agreed with the methodologies
and approaches used by EPA, they made a number of recommendations and
suggestions, and the Board asked specifically that the agency either
address them before this reassessment is released in 2002 or in a
future assessment of dioxins. The panels' recommendations generally
reflected either a consensus of the panelists or the opinion of a
majority. EPA generally addressed the panels' recommendations and
suggestions by performing additional analyses, adding or revising
text, identifying the recommendations or suggestions as related to
EPA's long-term research goals, or indicating that the data currently
available are not adequate to address the recommendation or
suggestion. Additional changes are now being made as EPA prepares the
draft for external interagency review.
Four of the five recommendations by the July 2000 panel regarded
improvements EPA could make to the section on health risks associated
with dioxins. The July 2000 panel recommended that EPA:
* explicitly explain the relationship between body burden and daily
intake, serum levels, and tissue dose;
* include a table in the final reassessment report summarizing the
various noncancer effects observed in animals and humans at low-level
exposures;
* improve the methodologies used in determining the cancer risks of
dioxins”such as requesting more detail on exactly how the cancer slope
factor[Footnote 34] for estimating cancer risks of the general
population was derived; and;
* reexamine the basis for its estimate of the upper bound cancer risks
to the general population.
The fifth recommendation of the July 2000 panel involved the use of
specific terminology in the exposure section. In addition, this panel
had several suggestions regarding the health risks associated with
dioxins, including that EPA:
* provide more detail in the Integrated Summary on the implications of
using the margin-of-exposure approach rather than comparing exposure
with reference doses;
* more clearly describe the significance of the upper bound cancer
risks to the public; and;
* add discussion of the uncertainties associated with using various
dose metrics specifically for evaluating childhood risks.
Ten of the 13 recommendations made by the Board panel also focused on
the need to improve the section on health risks associated with
dioxin. These recommendations included that EPA:
* calculate a reference dose to evaluate risk in addition to using the
margin-of-exposure approach to provide information on the minimum dose
that humans can receive without suffering harm,
* improve its margin-of-exposure approach by more clearly explaining
its choice to use dose levels associated with a 1-percent increase in
a particular effect and also by calculating a dose level associated
with the 10-percent increase more commonly used in chemical risk
assessments, and;
* provide better justification for using a specific dose metric and
identify the important data gaps that could affect the results of
those choices.
Three of 13 recommendations asked that EPA improve the section on
exposure to dioxins by evaluating the sources that contribute most to
dioxins in the food chain, discussing all "special population"
exposure in more detail, and extending breast-feeding exposure
scenarios beyond 1 year.
EPA made many additions and changes to the draft reassessment in
response to the peer review reports by both panels. For example, in
response to recommendations from both panels, EPA revised and added
text in several places to better explain the variety of dose metrics
available and why body burden is the best choice for assessing
dioxins, while acknowledging that EPA will need to address data gaps
on body burden in the future as further research is completed. Tables
1 and 2 in appendix IV highlight the actions EPA took to address both
panels' recommendations, suggestions, and concerns.
EPA and Peer Reviewers Do Not Agree on a Few Scientific Issues, and
Uncertainties Remain Because Data Are Lacking:
Overall, the peer review panels agreed with EPA's approach to the
reassessment, and EPA generally addressed the recommendations,
suggestions, and concerns of the peer review panels. In a few cases,
EPA disagreed with the panels' recommendations or suggestions. In
these cases, the agency explained its position in the text and, in the
case of the July 2000 panel, addressed it in a separate written
document. For example, although the Board panel had recommended that
EPA calculate a reference dose and add it to the text, EPA chose to
continue to use only the margin-of-exposure approach and not calculate
a reference dose. EPA stated in the revised draft report that a
calculated reference dose would be lower than most people's daily
exposure and added a more detailed explanation of why it chose to use
the margin-of-exposure approach.
In addition to disagreeing with EPA on a few key scientific issues,
the peer review panels could not agree among themselves in some cases
on EPA's findings. In such cases, the panels refrained from making
recommendations or suggestions to the agency. For example, members of
both peer review panels did not reach consensus on the strength of
evidence used by EPA to support the classification of TCDD as a human
carcinogen and other dioxin compounds as likely human carcinogens.
EPA officials believe that the weight of scientific evidence on human
and animal exposure supports classifying TCDD as a known human
carcinogen, a view also held by WHO and the U.S. Department of Health
and Human Services.
Although neither panel specifically recommended that EPA change its
classification of TCDD as a human carcinogen to a lesser category,
such as a likely human carcinogen, for various reasons most of the
peer reviewers did not endorse EPA's classification. For example,
while the July 2000 panel agreed that TCDD is clearly a potent
carcinogen in many species of animals, most of the panel thought that
human epidemiology studies were too limited, and the results not
consistent enough, to serve as a basis for showing increased cancer
mortality. As a result, the majority felt that the characterization of
TCDD as a known human carcinogen was not justified. Similarly, the
Board panel also noted limitations in the scientific data, questioning
the epidemiological data that indicated dioxins are carcinogens in
humans, as well as the data that supported similar modes of action
occurring in both animals and humans. Almost one-half of the Board did
not support classification of TCDD as a known human carcinogen for
various reasons. Those who did support the classification believed
that the results from studies of TCDD-exposed workers were persuasive
and that the variety of studies from researchers in different
countries provided limited but convincing evidence of TCDD's
carcinogenicity in humans.
Observations:
A decade in the making, EPA's draft reassessment report on dioxins was
both improved and limited by the passage of time, particularly in
estimating the daily dietary intake of dioxins by the typical American
adult. That is, EPA was able to include new food studies in the
reassessment as they became available. At the same time, however,
these and earlier studies that EPA relied on became less current with
the passage of time. Overall, while EPA's draft reassessment report
has advanced the state of knowledge on dietary exposure to dioxins in
the United States, the extent to which the estimate accurately
reflects current average daily exposure is not known. EPA acknowledges
the need for additional research on dietary intake, identifying a
number of data limitations associated with the estimates it developed
in its October 2001 draft report. Future efforts could eliminate most
of the food data limitations of the reassessment. Such efforts could
include periodic, comprehensive food surveys that analyze samples of
the most commonly eaten food products in each type of food studied,
with samples collected within the same time frames and analyses
performed using standardized methodologies. Further, when they become
available, the results of the ongoing EPA/USDA follow-up study on
dioxin levels in beef, pork, and poultry should provide quantitative
information on the changes, if any, in dioxin levels in these foods
from the mid-1990's to the present.
Agency Comments and Our Response:
We provided EPA with a draft of this report for its review and comment
and the draft segment comparing EPA's and WHO's assessments of dioxins
to WHO. In commenting on the draft report, EPA's assistant
administrator, Office of Research and Development, said that the
report was well researched and written and provided a balanced
treatment of the information. However, EPA believed that additional
information on some of the data limitations discussed in the section
on EPA's estimates of the dietary intake of dioxins would better
enable readers to evaluate the impact of the data limitations. Where
appropriate, we revised the report to reflect the views EPA presented
in its comments. For example, we added information concerning the
strength of the food concentration data used in estimating national
mean levels of exposure to dioxins, the sampling of animal fat rather
than meat and poultry products sold in grocery stores, and the
likelihood that current dioxin levels in food have significantly
declined since the mid-1990s. EPA's comments and our evaluation of
them are provided in appendix V.
In commenting on the draft segment comparing EPA's and WHO's analyses,
a senior advisor of health and environment, the Department of
Protection of the Human Environment, World Health Organization, said
the report was well written and accurate.
Scope and Methodology:
To describe the types and extent of data EPA used to reassess human
dietary exposure to dioxins in the United States, we reviewed the
relevant portions of the October 2001 draft reassessment, the 1994 and
2000 drafts that were peer reviewed, and the initial 1985 health risk
assessment. We also reviewed EPA documents and journal articles on the
agency's national sampling of beef, pork, and poultry samples, and
information about the other samples used for milk, eggs, fish, dairy
products, and vegetable fats. We discussed the samples and methodology
issues about them with EPA officials and contractor staff. We did not
validate or verify EPA's estimates of dietary exposure to dioxins.
To compare EPA's objectives, processes, analytical methods, and
conclusions with those of WHO, we analyzed EPA's October 2001 draft
reassessment report and various WHO publications on its objectives,
analyses, and conclusions. We discussed the similarities and
differences with EPA and WHO officials.
To determine the extent to which EPA's draft dioxin reassessment
reflects the views of two independent peer review panels, we analyzed
the recommendations, suggestions, and concerns in the reports by the
EPA Science Advisory Board's dioxin reassessment review subcommittee
panel”on reviews performed in 1994 and 2000”and a report from another
independent peer review panel on its July 2000 review. Recommendations
of the Board panel were noted in bold print in the executive summary,
and we considered other statements to be "suggestions" when they were
the consensus opinion of the panelists or the opinion of a majority or
of some of the panelists. We considered the July 2000 panel's
statements to be "recommendations," "suggestions," or "concerns," when
those particular words were used in the executive summary and where
the statements reflected either a consensus or the opinion of a
majority or of some of the panelists. We also reviewed EPA
documentation to determine the changes EPA has made to its draft
reassessment as a result of being peer reviewed, including comparing
the agency's previous drafts of the reassessment with each other and
reviewing the written responses to the July 2000 panel's
recommendations and suggestions. We also met with EPA officials to
identify the agency's responses to the panels' recommendations,
suggestions, and concerns, including discussing those with which it
disagreed.
We conducted our work from July 2001 through March 2002 in accordance
with generally accepted government auditing standards.
We will send copies of this report to the administrator, EPA, and make
copies available to others who request them. This report will also be
available on GAO's Web site [hyperlink, http://www.gao.gov].
If you or your staff have questions about this report, please call me
on (202) 512-3841. Key contributors to this report are listed in
appendix VI.
Signed by:
David G. Wood:
Director, Natural Resources and Environment:
[End of section]
Appendix I: Major Milestones in the EPA and WHO Dioxin Risk Assessment
Efforts:
1977:
WHO publishes initial cancer monograph that includes evaluation of
some dioxins.
Late 1970's-1984:
EPA performs initial risk assessments of the dioxin TCDD.
1985:
EPA releases first comprehensive health assessment document on dioxins.
1985-1987:
EPA reviews and adopts proposal to use interim toxic equivalency
factor (TEF) procedures for estimating risks associated with exposures
to mixtures of dioxins.
1987:
WHO updates previously released monographs on carcinogenicity of some
dioxins.
1988:
EPA completes external review draft on estimating cancer risks posed
by dioxins. Science Advisory Board completes review of external review
draft.
1990:
Experts at meeting in Bilthoven, Netherlands, establish a tolerable
daily intake for TCDD (WHO effort).
1991:
EPA begins current dioxin reassessment.
1991-1993:
EPA holds public meetings and workshops.
* 1991-92 - EPA holds public meetings.
* 1992 - EPA convenes two peer review workshops.
* 1993 - EPA holds a third peer review workshop.
1994:
EPA provides opportunities for public comment on draft report on human
health risks of dioxins (150-day comment period and 11 public
meetings). EPA submits draft report for Science Advisory Board review.
1995:
Science Advisory Board completes review of draft report, approving
most chapters but recommending revisions to some parts (EPA effort).
1997:
Dose-response chapter undergoes peer review (EPA effort).
WHO publishes new monographs, based on reassessments, on the evidence
for carcinogencity of TCDD and several other dioxins. Experts at
meeting in Stockholm, Sweden, derive consensus TEFs for dioxins for
human, fish, and wildlife risk assessments.
1998:
WHO publishes the consensus TEFs from the Stockholm meeting. Experts
meeting in Geneva, Switzerland, reevaluate the risks to human health
from dioxins and revise the tolerable daily intake for dioxins.
2000:
Science Advisory Board and an independent panel of peer reviewers review
major segments of EPA‘s revised draft report (EPA effort).
2001:
EPA completes final internal review draft report, which incorporates
revisions in response to Science Advisory Board and peer review panel
recommendations and comments.
Experts at meeting in Rome, Italy, evaluate risks associated with
dioxins in foods and establish a provisional tolerable monthly intake
for dioxins (WHO effort).
2002:
Dissemination of final dioxin reassessment report for review by other
federal agencies is pending. Publication of final dioxin reassessment
report is pending (EPA effort).
[End of section]
Appendix II: Comparison of the Major Conclusions from EPA's and WHO's
Dioxin Risk Assessments:
Effects associated with exposure to dioxins:
EPA conclusions:
Exposure to dioxins can produce a wide variety of effects in animals
(including cancer and noncancer health effects) and might produce many
of the same effects in humans.
EPA characterizes dioxin and related compounds as carcinogenic and
developmental, reproductive, immunological, and endocrinological
hazards and makes the following specific points.[A]
* Exposure to TCDD leads to an increased risk of generalized cancers
at multiple organ sites, including lung cancer.
* Long-term noncancer consequences of exposure to TCDD in adults
include chloracne, elevated gamma glutamyl transferase levels, and
altered testosterone levels.' Among the possible noncancer
consequences of exposure to TCDD or other dioxin and dioxin-like
compounds are dermatological conditions such as chloracne; liver
diseases; and kidney, nervous system, and lung disorders.
* Although available data suggest an association between TCDD exposure
and other adverse outcomes, further study is required of circulatory
and heart disease, diabetes and glucose metabolism, reproductive and
developmental outcomes, and immunologic disorders.
WHO conclusions:
Exposure to dioxins may be linked to a variety of adverse effects.
* Short-term human exposure to high levels of dioxins may result in
skin lesions (such as chloracne) and altered liver function.
* Long-term exposure is linked to impairment of the immune system, the
developing nervous system, the endocrine system, and reproductive
functions.
* Chronic animal exposure to dioxins has resulted in several types of
cancer. Human data from occupational or accidental exposure has
produced evidence of increased risks for all cancers combined, along
with less strong evidence of increased risks for cancers of particular
sites.
Mode of action through which exposure to dioxins can lead to adverse
effects:
EPA conclusions:
Dioxins are structurally related and elicit their effects through a
common mode of action”binding of dioxins to a cellular protein called
the aryl hydrocarbon receptor. Binding to the aryl hydrocarbon
receptor appears to be necessary for all well-studied effects of
dioxins but is not sufficient, in and of itself, to elicit these
responses.
TCDD and related compounds have a common mode of action in animals and
humans. Therefore, there is no reason to expect, in general, that
humans would not be similarly affected as animals at some dose.
WHO conclusions:
A broad variety of data has shown the importance of the aryl
hydrocarbon receptor in mediating the biological effects of dioxins.
The precise chain of molecular events by which the receptor elicits
these effects is not yet fully understood. However, alterations in key
biochemical and cellular functions are expected to form the basis for
dioxin toxicity.
Experimental data indicate that TCDD and probably other
polychlorinated dibenzo-p-dioxins (CDD) and polychlorinated
dibenzofurans (CDF) are not direct-acting genotoxic agents (i.e., do
not directly affect genetic material).
Dioxins act through the same mode of action in animals and humans.
Use of the toxicity equivalency (TEQ) concept:
EPA conclusions:
EPA and the international scientific community have adopted TEQ of
dioxins as prudent science policy.
(EPA recommended that the TEFs derived by WHO in 1997”published in
1998”be used to assign TEQ to complex environmental mixtures for
assessment and regulatory purposes.)
WHO conclusions:
The complex nature of CDD, CDF, and polychlorinated biphenyls (PCB)
mixtures complicates the risk evaluation for humans. The concept of
TEFs has been developed to facilitate risk assessment and regulatory
control of exposure to these mixtures.
(WHO derived updated consensus TEFs for 29 dioxins in 1997, with the
results of the meeting published in 1998. Subsequent WHO assessments
of dioxins used this updated set of TEFs for their calculations.)
Whether dioxins are human carcinogens:
EPA conclusions:
Complex mixtures of dioxins are highly potent, "likely" human
carcinogens.
* A weight-of-the-evidence evaluation suggests that mixtures of
dioxins are strong cancer promoters and weak direct or indirect
initiators and are likely to present a cancer hazard to humans.[C]
* Because dioxins and related compounds always occur in the
environment and in humans as complex mixtures of individual congeners,
it is appropriate that the characterization apply to the mixture.
Individual congeners can also be characterized as to their
carcinogenic hazards.
* TCDD is best characterized as "carcinogenic to humans." Based on the
weight of all evidence (human, animal, and mode of action), TCDD meets
the criteria that allow EPA and the scientific community to accept a
causal relationship between TCDD exposure and cancer hazard.
* Other individual dioxin-like compounds are characterized as "likely
to be human carcinogens" primarily because of the lack of
epidemiological evidence associated with their carcinogenicity,
although the inference based on TEQ is strong that they would behave
in humans as TCDD does. Other factors, such as the lack of compound-
specific chronic animal studies, also support this characterization.
WHO conclusions:
TCDD is a human carcinogen (group 1), considering limited evidence in
humans, sufficient evidence in experimental animals, and evidence of a
mode of action that functions the same way in humans as in
experimental animals.[D]
Other dioxins are not classifiable as to their carcinogenicity to
humans (group 3). Depending on the specific compound evaluated, the
International Agency for Research on Cancer (IARC) noted that the
available data provided inadequate evidence for carcinogenicity in
humans or limited evidence, inadequate evidence, or evidence
suggesting lack of carcinogenicity in experimental animals.
Whether there appears to be a "threshold" or safe dose of dioxins that
would not cause adverse effects:
EPA conclusions:
The supposition of a response threshold for receptor-mediated effects
(such as those associated with dioxins' binding to the aryl
hydrocarbon receptor ) is a subject for scientific debate. The same
receptor occupancy assumption of the classic receptor theory is
interpreted by different parties as support for and against the
existence of a threshold.
Empirical dose-response data from cancer studies do not provide
consistent or compelling support for threshold models and are
insufficient to move from EPA's default policy of linear extrapolation
(an approach that assumes there is no threshold of exposure without
risk).
Threshold levels of lifetime exposure to dioxins that would cause
toxic noncancer effects may be below the current level of background
exposure and body burdens, and, therefore, the potential exists for
noncancer risk at background exposure.
WHO conclusions:
TCDD does not affect genetic material, and there is a level of
exposure below which cancer risk would be negligible.
Although TCDD is classified by IARC as a human carcinogen, it is not
considered to be a direct acting carcinogen. Therefore, a threshold
approach could be used in the hazard assessment approach.
A tolerable intake can be established for TCDD on the basis of the
assumption that there is a threshold for all effects, including
cancer. Because cancer occurred in animals at higher body burdens than
other toxic effects, establishing a tolerable intake on the basis of
noncancer effects would also address any carcinogenic risk.
Whether it is useful to set a dose or exposure level that the public
could experience for a lifetime without expectation of harm:
EPA conclusions:
EPA did not calculate reference dose or reference concentration values
in this reassessment as it generally does for noncancer effects in
other assessments. Instead, EPA chose to characterize the margins of
exposure between estimated actual human exposure and the exposure
levels at which studies indicated various adverse noncancer effects
could occur.
WHO conclusions:
The WHO 1998 consultation set daily limits on exposure levels of
dioxins for non-cancer effects, a tolerable daily intake.
The Joint Expert Committee on Food Additives of the United Nation's
Food and Agriculture Organization and WHO set a provisional tolerable
monthly intake limit on exposure levels to dioxins, again focusing on
noncancer effects. The Committee participants felt that it was more
appropriate to express the tolerable intake on a monthly rather than a
daily basis because of the long half-life of dioxins (i.e., the body's
stored dioxins decline slowly, with only half of the accumulated
dioxins disappearing over about 7 years).
Human exposure to dioxins:
EPA conclusions:
Human exposure to dioxins has occurred through background exposure,
contamination of foods, occupational exposure, and exposure associated
with industrial accidents. An increased background exposure can result
from either a diet that favors consumption of foods high in dioxin
content or a diet that is disproportionately high overall in animal
fats.
Most (more than 95 percent) background exposure results from the
presence of minute amounts of dioxins in dietary fat, primarily from
the commercial food supply.
The average dioxin tissue level for the general U.S. adult population
appears to be declining.
Five compounds account for most (about 80 percent) of the toxicity in
human tissue concentrations.
WHO conclusions:
Human exposure to dioxins may occur through background (environmental)
exposure and accidental and occupational contamination.
Over 90 percent of human background exposure is estimated to occur
through the diet, with food from animal origin being the predominant
source.
Recent studies show decreasing levels of dioxins in food and
consequently a significantly lower dietary intake of these compounds.
Risks of adverse health effects at the general public's current levels
of exposure to dioxins:
EPA conclusions:
In general, EPA's assessments indicated that dioxins pose risks at
lower levels of exposure than previously estimated and that the
general public's current levels of exposure are at or near those that
have been observed to cause harm.
EPA estimates that the upper bound cancer risk at average current
background body burdens exceeds 10-3 (i.e., the upper bound on general
population lifetime risk for all cancers might be on the order of 1 in
1,000 or more). However, this is an upper bound estimate, so the true
risks are likely less than that and may be zero for most people.
* In 1985, EPA's estimate of the cancer slope factor based on exposure
to TCDD was 1.6 x 10-4 per picogram of TCDD per kilogram of body
weight per day (pgTCDD/kgBW/day).[E]
* EPA's current upper bound slope factor for estimating human cancer
risk on the basis of human data is 1 x 10-3 per pgTCDD/kgBW/day.
* EPA's current upper bound slope factor for estimating human cancer
risk on the basis of animal data is 1.4 x 10-3 per pgTCDD/kgBW/day.
EPA estimated that U.S. residents are exposed daily to about 1
picogram of dioxins per kilogram of body weight, which is close to the
level that caused biological changes in animals. EPA noted that the
margins of exposure between estimated actual human exposure and the
exposure levels at which studies indicated adverse noncancer health
effects could occur were "considerably less than typically seen for
environmental contaminants of toxicologic concern."
WHO conclusions:
In general, WHO's assessments also indicated that dioxins pose risks
at lower levels of exposure than previously estimated and that the
general public's current levels of exposure are at or near those that
have been observed to cause harm.
In 1990, WHO experts had established a tolerable daily intake for TCDD
of 10 picograms per kilogram of body weight. In 1998, the WHO
consultation established a tolerable daily intake for dioxins at a
range of 1-4 TEQ picograms per kilogram of body weight and noted that
subtle effects may already occur in the general population at current
background levels of 2 to 6 picograms per kilogram of body weight. The
consultation stressed that the ultimate goal is to reduce human intake
levels below 1 picogram TEQ per kilogram of body weight per day.
In 2001, Joint Expert Committee on Food Additives of the United
Nation's Food and Agriculture Organization of the United Nations and
WHO determined that a monthly tolerable intake level made more sense
than a daily level and established a provisional tolerable monthly
intake of 70 picograms per kilogram of body weight per month
(equivalent to 2.33 picograms per day) for dioxins.
The various WHO entities did not calculate quantitative cancer risk
estimates for the additional cancer risk that dioxins might pose to
the general population. However, WHO did explore the calculation of a
cancer "benchmark dose" (the dose or body burden estimated to result
in a 1-percent increase in cancer mortality) through various models.
On the basis of data from three industrial exposure studies, WHO
estimated that the body burden of dioxins associated with a 1-percent
excess cancer risk over a lifetime was 3 to 13 nanograms per kilogram
of body weight, which is associated with a daily dose of dioxins in
the range of 2 to 7 picograms per kilogram of body weight per day.
Risks to population subgroups:
EPA conclusions:
Children's risks from dioxins and related compounds may be greater
than that of adults, but more data are needed to fully address the
issue.
There may be individuals in the population who might experience a
higher cancer risk on the basis of genetic factors or other
determinants of cancer risk not accounted for in epidemiologic data or
animal studies. In particular, a very small percentage of the
population (less than 1 percent) may experience risks that are 2 to 3
times higher than the general population estimate if their individual
response is at the upper bound and they are among the most highly
exposed based on dietary intake of dioxins.
WHO conclusions:
Certain population subgroups are at greater risk from dioxins. Fetuses
are most sensitive to dioxin exposure, and newborns may also be more
vulnerable to certain effects. Some individuals or groups of
individuals may be exposed to higher levels of dioxins because of
their diets or occupations.
[A] Endocrinological hazards are those related to the system of
ductless glands that secrete hormones directly into the blood stream
for distribution throughout the body, such as the pituitary, thyroid,
and adrenal glands.
[B] Elevated gamma glutamyl transferase levels are among the changes
in liver function and structure that have been observed using human
data.
[C] According to EPA's revised proposed guidelines for carcinogen risk
assessment, the descriptor "likely to be a human carcinogen" is
appropriate when the available tumor effects and other key data are
adequate to demonstrate carcinogenic potential to humans, yet not
sufficient to infer a cause and effect relationship.
[D] For additional information on WHO-International Agency for
Research on Cancer's (IARC) evaluation categories and the definitions
of degrees of evidence, see the Preamble to the IARC Monographs
available on the IARC Internet site [hyperlink, http://www.iarc.fr/].
[E] The cancer slope factor is an upper bound of the probability of
cancer risk in the population. According to EPA, the slope factor
generally approximates or exceeds a 95-percent confidence limit,
meaning that there is a greater than 95-percent chance that cancer
risks will be less than the upper bound.
Source: GAO review of EPA and WHO documents on dioxin reassessment
efforts.
[End of table]
[End of section]
Appendix III: Questions EPA Asked Peer Review Panels to Address:
EPA sought expert opinions from both a July 2000 panel of independent
peer reviewers and a November 2000 Science Advisory Board expert panel
on several key questions that pertain to the content of the documents
under review. The questions are classified into 11 general topics.
Most of the questions are the same for both panels. However, according
to usual Science Advisory Board practice, EPA staff, Board staff, and
the chair of the Board's dioxin reassessment review subcommittee
jointly developed additional questions for the Board's review. Table 6
and table 7 show the topics and questions addressed by the July 2000
panel, and Board panel, respectively.
Table 6: Questions for the July 2000 Panel Review of EPA's Draft
Dioxin Reassessment:
Topic: Body burden;
Question: 1. Did EPA adequately justify its use of body burden as a
dose metric for inter-species scaling? Should the document present
conclusions based on daily dose?
Topic: Use of margin-of-exposure approach;
Question: 2. How might the rationale be improved for EPA's decision
not to calculate a reference dose/reference concentration, and for the
recommended margin-of-exposure approach for conveying risk
information? Is a margin-of-exposure approach appropriate, as compared
to the traditional reference dose/reference concentration? Should the
document present a reference dose/reference concentration?
Question: 3. Are the calculations of a range of effective dose (ED)01
body burden for noncancer effects in rodents responsive and clearly
presented? Please comment on the weight of evidence interpretation of
the body burden data associated with a 1 percent response rate for
noncancer effects that is presented in Chapter 8, appendix I and
figure 8-1 (where EPA considers that the data best support a range
estimate for ED01 body burdens from lOnh/kg to 50 ng/kg).
Topic: Mechanisms and mode of action;
Question: 4. How might the discussion of mode of action of dioxin and
related compounds be improved?
Question: 5. Despite the lack of congener-specific data, does the
discussion in the Integrated Summary and Risk Characterization support
EPA's inference that these effects may occur for all dioxin-like
compounds, based on the concept of toxicity equivalence?
Topic: TEFs;
Question: 6. Is the history, rationale, and support for the TEQ
concept, including its limitations and caveats, laid out by EPA in a
clear and balanced way in Chapter 9? Did EPA clearly describe its
rationale for recommending adoption of the 1998 WHO TEFs?
Question: 7. Does EPA establish clear procedures for using,
calculating, and interpreting toxicity equivalence factors?
Topic: Noncancer effects:
Question: 8. Have the available human data been adequately integrated
with animal information in evaluating likely effect levels for the
noncancer endpoints discussed in the reassessment?
Question: 9. Do reviewers agree with the characterization of human
developmental, reproductive, immunological, and endocrinological
hazard? What, if any, additional assumptions and uncertainties should
EPA embody in these characterizations to make them more explicit?
Topic: Cancer effects;
Question: 10. Do you agree with the characterization in this document
that dioxin and related compounds are carcinogenic hazards for humans?
Question: 11. Does the document clearly present the evolving
approaches to estimating cancer risk (e.g. margin of exposure and the
lower limit on ED01 as a point of departure) as described in EPA's
April 1996 "Proposed Guidelines for Carcinogenic Risk Assessment"? Is
this approach equally as valid for dioxin-like compounds?
Question: 12. Please comment on the presentation of the range of upper
bound risks for the general population based on this reassessment.
What alternative approaches should be explored to better characterize
quantitative aspects of potential cancer risk? Is the range that is
given sufficient, or should more weight be given to specific data
sources?
Topic: Background and population exposures;
Question: 13. Have the estimates of background exposures been clearly
and reasonably characterized?
Question: 14. Has the relationship between estimating exposure from
dietary intake and estimating exposure from body burden been clearly
explained and adequately supported?
Question: 15. Have important "special populations" and age-specific
exposures been identified and appropriately characterized?
Topic: Children's risk;
Question: 16. Is the characterization of increased or decreased
childhood sensitivity to possible cancer and noncancer outcomes
scientifically supported and reasonable? Is the weight-of-evidence
approach appropriate?
Topic: Relative risks of breast feeding;
Question: 17. Has EPA adequately characterized how nursing affects
short-term and long-term body burdens of dioxins and related compounds?
Topic: Risk characterization summary statement;
Question: 18. Does the summary and analysis support the conclusion
that enzyme induction, changes in hormone levels, and indicators of
altered cellular function seen in humans and laboratory animals
represent effects of unknown clinical significance, but they may be
early indicators of toxic response?
Question: 19. Has the short summary statement in the risk and hazard
characterization on page 107 adequately captured the important
conclusions and the areas where further evaluation is needed? What
additional points should be made in this short statement?
Topic: Sources;
Question: 20. Are these sources adequately described and are the
relationships to exposure adequately explained?
Source: EPA.
[End of table]
Table 7: Questions for the November 2000 Science Advisory Board Panel:
Topic: Body burden;
Question: 1. Did EPA adequately justify its use of body burden as a
dose metric for inter-species scaling? Should the document present
conclusions based on daily dose?
Topic: Use of margin-of-exposure approach.
Question: 2. Has EPA's choice of the margin-of-exposure approach to
risk assessment adequately considered that background levels of
dioxins have dropped dramatically over the past decade and are
continuing to decline? How might the rationale be improved for EPA's
decision not to calculate a reference dose/reference concentration,
and for the recommended margin-of-exposure approach for conveying risk
information? Is a margin-of-exposure approach appropriate, as compared
to the traditional reference dose/reference concentration? Should the
document present a reference dose/reference concentration?
Question: 3. Are the calculations of a range of ED01 body burden for
noncancer effects in rodents responsive and clearly presented? Please
comment on the weight-of-evidence interpretation of the body burden
data associated with a 1-percent response rate for noncancer effects
that is presented in chapter 8, appendix I and Figure 8-1 (where EPA
considers that the data best support a range estimate for ED01 body
burdens from lOnh/kg to 50 ng/kg).
Topic: Mechanisms and mode of action;
Question: 4. How might the discussion of mode of action of dioxin and
related compounds be improved?
Question: 5. Despite the lack of congener-specific data, does the
discussion in the Integrated Summary and Risk Characterization support
EPA's inference that these effects may occur for all dioxin-like
compounds, based on the concept of toxicity equivalence?
Topic: TEFs:
Question: 6. Is the history, rationale, and support for the TEQ
concept, including its limitations and caveats, laid out by EPA in a
clear and balanced way in Chapter 9? Did EPA clearly describe its
rationale for recommending adoption of the 1998 WHO TEFs?
Question: 7. Does EPA establish clear procedures for using,
calculating, and interpreting toxicity equivalence factors?
Topic: Noncancer effects;
Question: 8. Have the available human data been adequately integrated
with animal information in evaluating likely effect levels for the
noncancer endpoints discussed in the reassessment? Has EPA
appropriately defined noncancer adverse effects and the body burdens
associated with them? Has EPA appropriately reviewed, characterized,
and incorporated the recent epidemiological evidence for noncancer
risk assessment for human population?
Question: 9. Do reviewers agree with the characterization of human
developmental, reproductive, immunological, and endocrinological
hazard? What, if any, additional assumptions and uncertainties should
EPA embody in these characterizations to make them more explicit?
Topic: Cancer effects;
Question: 10. Do you agree with the characterization in this document
that dioxins and related compounds are carcinogenic hazards for
humans? Does the weight of the evidence support EPA's judgment
concerning the listing of environmental dioxins as a likely human
carcinogen?
Question: 11. Does the document clearly present the evolving
approaches to estimating cancer risk (e.g., margin of exposure and the
lower limit on ED01 as a point of departure) as described in EPA's
1996 "Proposed Guidelines for Carcinogenic Risk Assessment"? Is this
approach equally as valid for dioxin-like compounds? Has EPA
appropriately reviewed, characterized, and incorporated the recent
epidemiological evidence for cancer risk assessment for human
populations?
Question: 12. Please comment on the presentation of the range of upper
bound risks for the general population based on this reassessment.
What alternative approaches should be explored to better characterize
quantitative aspects of potential cancer risk? Is the range that is
given sufficient or should more weight be given to specific data
sources?
Topic: Background and population exposures;
Question: 13. Have the estimates of background exposures been clearly
and reasonably characterized?
Question: 14. Has the relationship between estimating exposure from
dietary intake and estimating exposure from body burden been clearly
explained and adequately supported? Has EPA adequately considered
available models for the low-dose exposure-response relationships
(liner, threshold, "J" shaped)?
Question: 15. Have important "special populations" and age-specific
exposures been identified and appropriately characterized?
Topic: Children's risk;
Question: 16. Is the characterization of increased or decreased
childhood sensitivity to possible cancer and noncancer outcomes
scientifically supported and reasonable? Is the weight-of-evidence
approach appropriate?
Topic: Relative risks of breast feeding;
Question: 17. Has EPA adequately characterized how nursing affects
short-term and long-term body burdens of dioxins and related compounds?
Topic: Risk characterization summary statement;
Question: 18. Does the summary and analysis support the conclusion
that enzyme induction, changes in hormone levels, and indicators of
altered cellular function seen in humans and laboratory animals
represent effects of unknown clinical significance, but they may be
early indicators of toxic response?
Question: 19. Has the short summary statement in the risk and hazard
characterization on page 107 adequately captured the important
conclusions and the areas where further evaluation is needed? What
additional points should be made in this short statement?
Topic: Sources;
Question: 20. Are these sources adequately described and are the
relationships to exposure adequately explained?
Source: EPA.
[End of table]
[End of section]
Appendix IV: EPA's Responses to Peer Review Panels:
EPA generally addressed the peer review panels' comments by performing
additional analyses, adding or revising text, or identifying comments
as related to EPA's long-term research goals. In some instances, EPA
thought that the reassessment already addressed the panel's comment.
The panels classified their recommendations, suggestions, and
concerns, and EPA responded to each. Tables 8 and 9 show the comments
made by the panels and EPA's response or action taken.
Table 8: EPA's Responses to July 2000 Panel's Report:
Recommendation:
1. Use terminology such as "ambient exposures" or "general population
exposures," rather than the term "background exposure," which implies
normal and acceptable.
EPA response or action:
EPA prefers to use "background exposure" as it appropriately
recognizes the ubiquitous nature of trace amounts of dioxins in the
environment and food supply even when no sources are identified
nearby. EPA added a definition to its glossary.
Recommendation:
2. Present more detail (e.g., sample calculations) in the Integrated
Summary on exactly how the cancer slope factor was derived.
EPA response or action:
Additional information has been added to Section 5 of the Integrated
Summary to clearly illustrate how the cancer slope factors were
derived.
Recommendation:
3. The panel thought that the upper bound cancer risk of 10-3 to 10-2
in the general population, implying an additional 3,000 to 30,000
deaths per year, was alarmist, not warranted and not realistic.
EPA response or action:
Recommended that EPA should present "reality check" on the risk
estimates relative to highly exposed past cohorts.
EPA states its estimates were derived from the best data sets
available.
Recommendation:
4. Include a table to summarize the various noncancer effects observed
in animals and humans at low-level exposures.
EPA response or action:
EPA has added a table (table 2-2) to the Integrated Summary of the
September 2000 draft. While not extensive, it illustrates the low
range of margins of exposure that is calculated for a variety of
effects in several species, including humans.
Recommendation:
5.The panel thought body burden was an appropriate dose metric.
However, the panel recommended that EPA explicitly explain the
relationship among daily intake, serum levels, tissue dose, and body
burden.
EPA response or action:
Additional discussion of alternative dose metrics has been included in
the Health Assessment of TCDD and Related Compounds (Part II), Chapter
1: Disposition and Pharmocokinetics. This discussion has also been
carried over to Section 1.3 of the Integrated Summary. The utility,
strengths, and weaknesses of each are presented, and in a number of
cases the relationships of one to another are discussed.
Suggestion:
1. Data presented on dioxin levels in food are an improvement over
earlier drafts, but need more specific information on the number of
samples collected, sampling locations, and standard deviations of
observed levels presented in tables 4-6 and 4-8.
EPA response or action:
This additional information was included in Estimating Exposure to
Dioxin-Like Compounds (Part I), Vol. 3, Chapter 4, and has been now
added to the Integrated Summary (see table 4-5). This table presents
dioxin levels in environmental media and food, along with number of
samples, mean, range, and standard deviation.
Suggestion:
2. Revise and expand discussion of dioxin levels in food, identifying
levels of dioxins in other food sources for which data are available;
listing food sources that have not been extensively characterized
(i.e., fish); commenting on changing rate of dioxins in food sources
over the years; and addressing the effects of cooking practices.
EPA response or action:
Several new paragraphs have been added/edited in the Integrated
Summary, Section 4, to address these comments.
Suggestion:
3. Reviewers thought EPA adequately derived approaches to estimate
average daily dose from both dietary intake and body burden. Suggested
revisions included (a) providing a clear definition of body burden and
explaining how body burden relates to tissue levels; (b) presenting
equations and sample calculations in the Integrated Summary to
illustrate how average daily dose can be estimated from dietary intake
or from body burden; (c) considering other sources of data for
characterizing trends in body burden levels; and (d) providing
additional detail on the variability in the distribution of estimated
average daily intakes.
EPA response or action:
(a) EPA added a definition of body burden, and an explanation of how
body burden relates to tissue levels, to the glossary in the
Integrated Summary; (b) equations illustrating how average daily dose
can be estimated from dietary intake or from body burden were in Part
I, Vol. III, Chapter 4, but were not included in the Integrated
Summary in the interest of brevity; (c) although body burden trends
(e.g., differences in age) in the reassessment document are not
statistically based, a current modeling study is underway to more
fully understand body burden trends; (d) section 4.4.3 in the
Integrated Summary on variability in intake levels has been expanded
to include key references and a new discussion on the Center to
Disease Control and Prevention blood study to further support the
findings on variability. EPA is also currently investigating the
possibility of using probability methods to further study variability
of dioxin exposure.
Suggestion:
4. Reviewers thought EPA identified important "special populations" of
highly exposed individuals and suggested that the agency consider
including others, such as people who lose weight rapidly, fetuses, and
people who eat large amounts of potentially contaminated food sources
not explicitly considered in the reassessment (e.g., lamb).
EPA response or action:
In Part I, Vol. III, Chapter 5, EPA analyzed a large amount of
available data on these special populations: nursing infants (Section
5.2), people who fish (Section 5.3), people living near sources of
dioxin release (Section 5.4), and cigarette smokers (Section 5.5).
Other populations (such as exposed workers or those living in Seveso)
were discussed in detail in Part II.
Suggestion:
5. Reviewers thought EPA may have overstated upper bound risks and
suggested EPA more clearly describe the basis of the current cancer
slope factor and significance of upper bound cancer risks to public.
EPA response or action:
The text has been revised to put the upper bound estimate of risk in
better perspective. The previous range of upper bound risks was
apparently confusing and has been removed.
Suggestion:
6. Most reviewers agreed that developmental, reproductive,
immunological, and endocrinological noncancer effects could be seen in
humans, given sufficient dose. Reviewers suggested EPA improve the
justification for the conclusion that human epidemiological data
suggest that noncancer effects occur at ambient exposures.
EPA response or action:
Additional discussion has been added to Sections 2,5, and 6 of the
Integrated Summary to address this issue.
Suggestion:
7. The panel thought the Integrated Summary presented a reasonable
argument that cancer risk associated with breastfeeding is likely low
and suggested EPA provide similar argument for noncancer effects.
EPA response or action:
EPA asserts that the argument that noncancer risk associated with
breastfeeding is also low is already in the report, although it is not
broken out into a separate section. EPA agrees with WHO that on
balance, the benefits of breastfeeding outweighed risks of dioxin
exposures.
Suggestion:
8. The panel agreed that the Integrated Summary needs additional
discussion on the uncertainties associated with using various dose
metrics specifically for evaluating childhood risks. Some reviewers
continued to have reservations about EPA's selection of the body
burden dose metric for children, especially considering that
children's (especially nursing infants') doses can be much higher than
those of adults, even though their body burdens often are not.
EPA response or action:
See recommendation above relating to selection of a dose metric.
Figures 4-4 and 5-2 were added to the Integrated Summary to help
illustrate the rationale for selecting body burden as the dose metric
using a nursing scenario, and expanded discussion can be found in
Section 4. Nonetheless, uncertainty remains regarding the most
appropriate dose metric for any given effect.
Suggestion:
9. Most of the reviewers agreed with the use of margin of exposure to
express exposures rather than comparing exposures with reference dose
given the assumptions made in the assessment, but they suggested the
implication of these assumptions be more clearly defined.
EPA response or action:
Additional discussion regarding the concept of margin of exposure has
been included in Sections 5 and 6 of the Integrated Summary. A table
has been added to illustrate the concept for several cancer and
noncancer endpoints. Additional details have been added to the
discussion regarding the decision to use a margin of exposure rather
than calculate a reference dose.
Suggestion:
10. The reviewers thought the Integrated Summary clearly presented the
entire data set of dose response data that met EPA's selection
criteria, but that presentation should be improved. Many thought that
EPA should attempt to differentiate effects that are "frank
manifestations of toxicity" from effects with unknown clinical
significance.
EPA response or action:
Additional discussion has been added to the text to provide this
differentiation, as suggested by the peer reviewers. EPA believes
differentiating effects is inherently difficult since the
manifestations of toxicological response lie along a continuum and
biochemical changes may serve as a biomarker of the potential for
frank response.
Suggestion:
11. The reviewers generally agreed that Chapter 9 on TEQs in Part II,
presented the history, rationale and support for the TEQ approach for
evaluating dioxin toxicity, but they were concerned that this approach
attributes dioxin toxicity to compounds for which few toxicologic data
are available. Though the reviewers felt that Chapter 9 establishes
clear procedures for using, calculating, and interpreting TEQs, they
stated certain topics needed to be described more clearly and
suggested EPA concisely state why it selected WHO's 1998 TEFs over
previously used TEFs, present example TEQ calculations as an appendix,
and should stress that risk assessors should characterize fate and
transport of individual dioxins separately.
EPA response or action:
Chapter 9 on TEQs has been revised in response to peer reviewers'
comments. Additional discussion has been added to the Chapter to focus
on 5 compounds that make up greater than 70 percent of human exposure
and body burden on a TEQ basis. While several of the minor compounds
have limited toxicologic data supporting their TEF values, the major
compounds have robust data sets. This discussion has been carried over
to the Integrated Summary in Section 1.2.
Source: EPA.
[End of table]
Table 9: EPA's Responses to Science Advisory Board Panel's Comments:
Recommendation:
1. Carry out additional work on the exposure assessment section to
evaluate sources that make the greatest contribution to dioxins in the
food chain, and make the text consistent with the tables.
EPA action or response:
This is a long-term research goal of EPA. EPA officials stated that
they interpret the Science Advisory Board recommendation as basically
endorsing what EPA plans to do in the future”linking sources of
dioxins with exposures. The minor issue regarding making the table and
text consistent was resolved by EPA.
Recommendation:
2. Include discussion of all "special population" exposures in the
summary document.
EPA action or response:
EPA added additional information regarding "special population"
exposures (i.e., some Native American subsistence fishers could be
highly exposed to dioxins depending on the amount of fish they catch
and where). According to EPA officials, the agency now addresses this
issue in the Integrated Summary”Sections 4 (exposure) and Section 6
(risk characterization) and specifically mentions Native Americans in
the text.
Recommendation:
3. Extend breastfeeding exposure scenarios beyond 1-year.
EPA action or response:
According to EPA officials, they performed additional analysis and
revised the related text. See Integrated Summary, Section 6.
Recommendation:
4. For human carcinogen designation, better understanding and
interpretation of epidemiological data are needed. Add expected
differences in results between epidemiological studies of genotoxic
agents and cancer promoters.
EPA action or response:
EPA added text in Part II and the Integrated Summary regarding the
expectations for epidemiological studies for strong cancer promoters
and will be including a discussion of new cancer studies in the
reassessment to provide the latest on this issue.
Recommendation:
5. Methodology: Agree with use of margin-of-exposure approach, but in
addition calculate a reference dose.
EPA action or response:
EPA disagreed and chose not to calculate a reference dose, but
explanation of why it did not explained in more detail. See pp. 118-
122 in the Integrated Summary.
Recommendation: 6.
Methodology: In future reevaluations develop quantitative estimates of
noncancer risk-”similar to those developed for cancer”-to the extent
methods become feasible.
EPA action or response:
EPA's opinion is that to some extent it is already merging cancer and
noncancer methods using margin-of-exposure analysis for both cancer
and noncancer effects. The text tries to balance the discussion of
cancer and noncancer risks, but noncancer risks cannot be done
quantitatively.
Recommendation:
7. Further investigation of noncancer hazards is needed. They receive
insufficient attention on pp. 7 and 11. About half of the panel
believes that the current draft assessment may overestimate the likely
cancer hazard.
EPA action or response:
EPA revised the text to put noncancer effects into better perspective,
but officials acknowledged that the tools used to describe cancer
risks are easier for people to understand. In the text of the report,
EPA is providing more discussion on noncancer effects by providing
examples where possible.
Recommendation:
8. The panel agreed with using body burden as the dose metric;
however, better justification for using a specific dose metric such as
body burden is needed. Provide more explicit examples of how different
dose metrics might apply to specific toxic endpoints.
EPA action or response:
EPA officials said that the agency has revised and added text in
several places to better explain the variety of dose metrics available
and why body burden is the best choice for assessing dioxin. EPA
revised Part II, Chapter 1 on dose metrics and it also made changes to
Chapter 8 and added text in the Integrated Summary, Sections 1,5, and
6. EPA recognized the need to better explain that using other dose
metrics rather than body burden in certain situations is also
acceptable.
Recommendation:
9. EPA should identify important data gaps on body burden (i.e., how
it varies with age and in females depending on number of offspring) to
highlight research opportunities.
EPA action or response:
EPA officials stated that research opportunities in the future will
address this issue. EPA will be incorporating new studies in future
dioxin assessments, particularly those that look at population
dynamics (i.e., younger people starting now with lower intake levels/
body burdens than in past) as they become available. Currently, there
is major work under way at the Center for Disease Control and
Prevention looking at serum levels regarding dioxins and other health
issues that will give insight/data on body burdens. First-year data of
3-year study have been collected.
Recommendation:
10. There is some evidence that very low doses of dioxins may result
in some decreases in adverse responses but can produce other adverse
effects at the same or similar doses. Evaluate the totality of the
evidence for non-monotonic dose response as studies become available,
particularly evidence for any "U-shaped" dose response curve.
EPA action or response:
EPA officials stated that the agency will continue to work on the dose
response chapter. The possibility that dioxins are anti-carcinogen is
reflected in the Integrated Summary, Section 2 with three Kayajanian
references. However, EPA does not have data on where or if it occurs
on the dose response curve”above or below body burdens.
Recommendation:
11. Calculate ED using definitions other than that used for ED01 and
for comparison purposes present values of ED10 (since its been applied
to other chemicals by the agency).
EPA action or response:
EPA has done additional analysis using other effective dose values
(e.g., ED10). EPA officials stated that it differed from the original
calculation using ED01 in only a few instances. See pp. 118-122, in
Integrated Summary and Part II, Chapter 8.
Recommendation:
12. Give additional consideration to its justification of method
selection for condensing these effective doses into a recommended
range.
EPA action or response:
See #11 above.
Recommendation:
13. The agency's description of its calculation of ED01 was not
sufficiently detailed to permit the calculations to be repeated.
Describe calculation of ED01 more clearly and completely.
EPA action or response:
More explanation provided for use of ED01. See #11 above.
Suggestion:
1. The agency's calculation of the cancer potency factor is not
prominently featured in the reassessment. Highlighting this
calculation would significantly improve the transparency and
accessibility of the reassessment.
EPA action or response:
EPA officials disagreed with the comment that cancer potency factor
not prominently featured. EPA officials stated that figure (5-2) on
cancer potency estimates for animal studies with full page footnote
provided in version reviewed by the Science Advisory Board. Text has
been added in Part II, Section 5 discussing sensitivity of
calculations.
Suggestion:
2. The panel suggested that the agency consider making greater and
more systematic use of parametric methods in calculations. This
approach would help readers to develop a better sense of how the
results presented depend upon specific analytical assumptions.
EPA action or response:
EPA does not plan to perform additional analysis. This is mostly
intended as a recommendation to do further research.
Concern:
1. The majority of panel members have concerns about Agency cancer
risk estimates associated with current population exposures and feel
that it was not appropriate for the agency to characterize the risks
in such a quantitative manner without providing a similar quantitative
estimate of uncertainty.
EPA action or response:
EPA has added text on what EPA can say about quantifying uncertainty.
EPA officials agree with the Science Advisory Board that there needs
to be improvements in methodology (i.e., it will require more/better
data sets). However, this will require further research in the future.
It is a generic concern, not just regarding dioxins.
Source: EPA.
[End of table]
[End of section]
Appendix V: Comments from the Environmental Protection Agency:
Note: GAO comments supplementing those in the report text appear at
the end of this appendix.
United States Environmental Protection Agency:
Office Of Research And Development:
Washington, D.C. 20460:
April 17 2002:
Ms. Christine Fishkin:
Assistant Director:
Natural Resources and Environment:
United States General Accounting Office:
Washington, DC 20548:
Dear Ms. Fishkin:
I am writing in response to an April 5, 2002 letter from David G.
Woods to EPA Administrator Christine Todd Whitman transmitting the
draft General Accounting Office (GAO) report entitled, Environmental
Health Risks: Information on EPA's Draft Reassessment of Dioxins (GAO-
02-515) for Agency review. Thank you for the opportunity to provide
our comments on this report before it is issued in final form. I
realize that this report is the culmination of a significant effort by
you and your colleagues. You should be commended for your thorough
researching of the questions posed to you and your balanced treatment
of the information at your disposal. This 67 page report deals with
technically complex issues which you have succeeded in presenting in a
concise and logical document. Your involvement of Agency experts in
the information gathering and drafting phases of this report has no
doubt added to its success and I compliment their efforts as well.
While the Agency is very pleased with this draft report. Some of the
points made by the Agency have not found their way into this review
draft. The Comments provided below represent a series of issues where
additional Agency comment is considered necessary. We have also
provided a mark-up noting minor or editorial corrections for your
consideration. These comments are not meant to detract from the
overall quality of the report but are presented for clarification and
completeness.
1) Apparent inconsistencies among different components of the Draft
Reassessment Documents: The GAO was supplied with internal working
copies of all components of the draft EPA dioxin reassessment. [See
comment 1] Each of these components was undergoing revision in
response to comments from an independent peer review panel and the EPA
Science advisory Board (SAB). At the time of the GAO review, different
components were at different stages of revision. The exposure
information contained in the Risk Characterization is a summary of
information and analysis presented in the Exposure and Health Volumes.
Since the development of the working draft of Characterization follows
development of the working draft of the Exposure and Health Volumes,
some inconsistences are inevitable. Among the changes made in the
Exposure Volume that were identified as inconsistences by the GAO are
the refinement of the fat content of ingested products, and the
introduction of an additional category of consumption called "other
meats". Clearly, it is EPA's intent to make the documents fully
consistent at publication. In identifying these inconsistencies
without clearly explaining the sequential nature of the revision
process, the GAO report could lead some readers to interpret these as
significant flaws rather than simply an issue of the draft
Characterization not yet reflecting the updated Exposure Volume. The
locations and text in question follows:
a. Footnote on p. 8: "EPA's Integrated Summary (Table 4-7) presents
information on exposure to 9 foods...." Table 4-7 in the draft
Integrated Summary had not been updated yet.
b. p. 19: The Integrated Summary does not reflect the newer and more
valid percentages of fat in the food products found in the Exposure
Volume.
c. p. 22: The Integrated Summary does not include corrected average
percent fat in milk found in the Exposure Volume.
2) Characterizing potential sources of uncertainty in the draft
Reassessment's dietary exposure estimate: The GAO draft correctly
identifies several sources of potential uncertainty in the
reassessment's estimate of dietary exposure. Each of these
uncertainties is also identified in the draft reassessment. In our
view, this point is not emphasized sufficiently in the GAO draft
report. [See comment 2] More importantly, the GAO report does not
provide the reader with enough perspective to judge the relative
significance of these uncertainties to the overall calculation of
dietary exposure. Without such a discussion, many readers would
reasonably conclude that the uncertainties are of significance;
otherwise, GAO would not have emphasized them. This is not
the case. Three issues are of particular importance are: a. The
strength of the food concentration data for deriving national mean
levels of exposure; b. The sampling of adipose tissue rather than
muscle tissue in the meat surveys; and, c. The likelihood that current
dioxin levels in food have significantly declined since the mid-
nineties. [See comment 3] EPA does not believe that these three issues
raised are major weakness in the dietary exposure calculation. EPA has
discussed in detail each of these issues with the GAO review team.
However, the current draft of the GAO report does not adequately
capture the depth of those discussions. A more detailed discussion of
these issues follows.
a. The draft GAO report states on p. 11, [Now on p. 10, See comment 4]
1st sentence in second paragraph: "... dioxins vary and acknowledged
that the available studies generally were not designed to estimate
national exposures." This is incorrect. The reassessment's dietary
estimate for beef, pork, and poultry are all based on joint EPA/USDA
studies which incorporated a rigorous statistical design specifically
intended to derive a representative national mean concentration.
Estimates for milk and dairy were based on an EPA milk survey that had
broad national coverage. Although not a statistically based sampling,
the study was specifically intended to gather milk samples that were
representative of typical milk consumed in the US. Fish and shellfish
accounted for an additional 26% of national exposure and this analysis
relied on data from a wide variety of sources not intended to develop
a national mean. Data on eggs, which the GAO study reviews in detail,
account for only 4% of the total and were not part of a formal
national survey. Together beef, pork, poultry, milk and dairy account
for 66% of total estimated exposure; consequently, a majority of the
dietary exposure estimated by EPA was derived from studies
specifically designed to estimate national exposures. Fish is the one
major food category, not based on sampling, designed to generate a
national exposure mean.
b. p 12, 2nd bullet and p. 17, 1st bullet: Concern is expressed about
the comparability of grocery store samples and the fat reservoir
samples taken for beef/pork/poultry in the national surveys: "Some of
the samples are of edible food products sold in grocery stores, while
others are of inedible cuts of fat, such as back fat on cattle...."
The three national surveys obtained back fat from cattle, leaf fat
from poultry, and belly fat from pork for the reasons this report
cites on p.17. "EPA used this approach because USDA federal inspectors
could obtain the samples with little disruption to the slaughtering
establishments and because the samples' high fat content would enable
more accurate measurement of dioxins, since the analysis would be of
highly concentrated fat samples....EPA concluded that the fat samples
for all three foods were comparable." [Now on p. 14; See comment 5]
The use of the term 'inedible fat' may be misleading to some readers.
The term, as used in the reassessment, refers more to the
marketability of the fat rather than its physiological or nutritional
status. For example, the back fat taken from beef carcasses is the
same fat reservoir that extended to the ribs, which is considered
edible fat. The critical issue is whether the lipid-adjusted
concentrations of dioxin-like compounds of the sampled adipose tissues
are good indicators of the lipid adjusted concentrations found in
muscle tissues regularly consumed in the US diet. EPA has concluded
the answer to this question is an unequivocal yes. There is a well
developed understanding of distributional behavior of dioxin-like
compounds in vertebrate tissues. In general, dioxin-like compounds
distribute readily across the fat reservoirs of an organism, based on
tissue lipid concentration. This understanding served as an essential
component of support to the reassessment's broader conclusion that
body burden is the best dose metric for estimating risk. This position
was endorsed by the EPA, SAB and is also the position adopted by the
WHO.
EPA chose to further support this understanding by specifically
examining dioxin distribution in beef cattle. The GAO draft report
discuses this study on p. 17, [Now on p. 16; See comment 6] stating
that "For the five samples, the ratios of CDDs. and CDFs in muscle fat
to CDDs and CDFs in back fat varied by up to 300 percent, ranging from
0.58 to 1.7; and the ratios for PCBs varied by up to 50 percent, from
1.0 to 1.5. This variability indicates that using fat samples
may overstate or understate dioxin levels in beef, pork, and poultry
to some extent." This GAO interpretation fails to adequately take into
consideration the inherent variability that comes from trying to
measure 0.000000000001 grams of dioxin in a gram of fat. Given the
complexities of dioxin laboratory analysis, back fat concentrations
ranging from 1/2 to 2 times the concentration in edible fat is best
characterized as indistinguishable from each other. The full weight of
evidence provides strong support for the use of back fat data to
calculate dietary intakes for beef.
c. The Draft GAO review correctly reports that most of the food
concentration data used in the reassessment were collected between 5
and 8 years ago and that since that time emissions from regulated
sources are anticipated to have declined (P11 first bullet and
footnote 10, p 44 observations). On page 45, [Now on p. 37; See
comment 7] the draft report concludes that "the extent to which
estimates accurately reflect current average daily exposure is not
known". EPA believes that sufficient information is available to
support a conclusion that, in spite of the emission reduction of the
late 1990's, the exposure estimates of the draft reassessment are a
reasonable characterization of contemporary exposure. The dioxin
reassessment emissions inventory estimates that, from 1987 to 1995,
overall quantifiable releases to the environment decreased by 75%.
Most of this reduction was from municipal and medical waste
incinerators and from pulp and paper facilities use of chlorine
bleach. These reductions were, in large part, in anticipation of EPA's
promulgation of regulations scheduled for the last half of the 1990's.
EPA has projected that full implementation of these rules would result
in an overall decrease in quantifiable emission from the 1987 baseline
of 90% or an additional 15% increment over the 1995 decline level.
Most of the food samples were taken after the initial 75% decrease had
occurred and therefore much of the decrease should already be
reflected in the food concentration numbers. Additionally, most of the
municipal and medical waste incinerators are located far from, and
down-wind from, concentrated meat and dairy production areas;
consequently, the impact of these emissions reduction on the
commercial food supply should be less than directly proportional to
their reduction in overall environmental release. Finally, reservoir
sources of dioxin-like compounds (old releases that have been stored
in soil and sediment and then reintroduced to the environment) are
estimated to account for half or more of current exposure. This,
combined with the unquantified sources of dioxin that cannot be
accounted for in the inventory estimate, tend to reduce the likelihood
of emission reduction in the late 90's significantly affecting the
current estimate of general population exposure via the commercial
food supply. EPA has concluded that, looking at the full weight of the
evidence, exposure estimates based on food concentrations for the mid-
1990's should be representative of current dietary exposure.
3) Variability in dairy concentration data: On p. 22 GAO, correctly
describes the variability in dairy products reported in the Oct.
draft. EPA has reviewed this number and concluded that since dairy
lipid-adjusted concentration is derived directly from the milk data it
should not have a separately derived standard deviation. The milk
values are as reported in the GAO review (0.18 plus or minus 0.0012).
This change was verbally reported to the GAO review team. [See comment
8]
4) Exclusion of elevated poultry samples form mean concentration
calculation: Page 18 of the draft GAO report reads: [Now on p. 15; See
comment 9] "EPA considered the two poultry fat samples inappropriate
for the dioxins study, which was aimed at identifying typical
exposures to dioxins. However, it is not clear that the poultry
samples with high concentrations of dioxins were anomalies because the
incidence of dioxin contamination in animals feeds is not known." EPA
has reported to the GAO review team that the cause of the high poultry
samples was specifically determined to be because of localized use of
ball clay as an anti-caking agent in soybean meal. That ball clay is
no longer being used (voluntarily removed after a FDA request to feed
manufacturers). EPA concluded it was inappropriate to extrapolate the
ball clay samples nationally to describe current background exposures
via consumption of poultry. EPA is currently drafting a new section on
animal feed contamination episodes, to include more details of this
episode.
5) Percentage of fat in consumed product: On p. 15, 2nd bullet, GAO
states that, "...specific information on the assumptions and analyses
EPA used in estimating these average fat percentages is not provided
in the draft reassessment report." On p. 19, this same point is made,
but in more critical detail. This is not correct. On p. 3-73 of the
draft Exposure Volume, EPA provides the following explanation for
their procedure for estimating percentage fat in consumed beef: [See
comment 10]
The percentage of fat in beef was estimated using food consumption
data and fat content data for various beef products provided by David
Haytowitz, USDA, to Linda Phillips, Versar, Inc., by personal
communication, January 2001. USDA obtained food consumption data from
the 1994-96 Continuing Survey of Food Intake Among Individuals
(CSFII). The total quantity (in grams) of each food item eaten by the
survey population in one survey day was tabulated and weighted to
represent the quantity eaten by the entire U.S. population in one day.
The fat content of each of these food items was also reported. To
estimate the weighted mean percent of fat in beef products that are
typically consumed by the U.S. population, the total amount of each
beef item was first multiplied by the fraction of fat reported for
that item to calculate the amount of beef fat consumed from each beef
item. Next, the total amount of beef fat consumed (in grams) was
calculated by summing the beef fat intakes for the individual beef
items. The total amount of beef consumed was also estimated by summing
the beef intake for the individual beef items. Finally, the weighted
fraction of beef was estimated by dividing the total beef fat intake
by the total beef intake. An abbreviated (i.e., the total number of
beef items included in the analysis was 146; only a few beef items
were included in the example to demonstrate the methodology) example
of this calculation is provided in Table 3-39.
It was also stated that the same source of data and procedure was
followed for poultry and pork, though without this much detail. EPA is
considering adding this information as an appendix to the Exposure
Volume.
6) Comparison of dietary intakes with body burden: The GAO report
focuses on the reasonableness of the dietary intake estimates by
examining the uncertainties in national food level data and dietary
intake assumptions. There is, however, an additional analytic approach
provided in the reassessment to assess the reasonableness of dietary
estimates that is not acknowledged by the GAO. This is the comparison
of projected intake levels to body burden measurements. For persistent
bioaccumulating compounds, scientists can use human tissue
measurements (blood serum) and pharmacokinetic modeling to estimate
cumulative exposure. Using this approach, the reassessment concludes
that when past elevated environmental levels are taken into
consideration there is strong agreement between current measured serum
levels and current estimated dietary exposure.
7) Instances of data not supplied in the draft report:
a. Other meats: On p. 13 and the footnote on p. 15, it is stated that
EPA did not provide data on the concentration and composition for
"other meats". The footnote on Table 430 from the October 2001 draft
states that the concentration of 0.18 ppt assigned to "other meats"
was, "estimated as the average of beef, pork, and poultry." The
justification and exact procedure for doing this will be included in
the final draft of the Exposure Volume.
b. Number of samples in composite for PCB analysis: On p. 14, it is
noted that, "The draft reassessment report does not specify the number
of individual samples in the composite samples" for egg, fish,
freshwater fish and shellfish, and vegetable. All these data was from
two publications from Mes, and Mes and Weber. These individuals did
not specify in their publication how many samples were in the
composites. A sentence will be added to the description of the data
stating that they did not identify how many samples were in the
composite.
8) Peer Review Process: Page 4, para 2, line 4 of the draft GAO report
reads "12 reviewers assembled by EPA" . The reviewers are not chosen
by EPA, but by an independent contractor (as noted by GAO later). It
is important to be clear that in all instances, peer reviewers were
chosen by an outside party, not EPA, in keeping with EPA's Peer Review
Guidance. [See comment 11]
9) TEF Values: The TEF for 2,3,4,7,8-PeCDF is 0.5. Therefore, the
statement in the 4th line from the end of the middle paragraph on page
6 of the draft GAO report needs correction to note that PeCDD has a
TEF of 1.0, PeCDF has a TEF of 0.5; all the others have TEFs of 0.1 or
lower. [Now on p. 6; See comment 12]
On p.25, last line of 1st paragraph, the GAO Report suggests that TEFs
for cancer rely on non-cancer endpoints. TEFs are relative potency
factors which are independent of endpoint. This is a basic
underpinning of the entire TEF approach. All data are considered,
according to a weighting scheme derived by international consensus and
based on scientific judgment, in setting TEFs. While EPA recognizes
that there are few long term carcinogenesis studies for
other dioxins, there are many studies of tumor promotion data
demonstrating that the TEFs work for that endpoint. GAO, EPA and peer
reviewers of the EPA reassessment have recognized that further
research on TEFs for dioxin and related compounds is needed. Some of
this work is ongoing and will provide input into future TEF updates.
[Now on pp.20-21; See comment 13]
In conclusion, I want to reiterate that the above mentioned discussion
is meant to provide clarification and completeness to a well
researched and written report Thank you for the opportunity for the
Agency to provide these comments as the GAO moves toward finalizing
its Report.
Sincerely yours,
Signed by:
Paul Gilman:
Assistant Administrator:
Attachment:
The following are GAO's comments on EPA's letter dated April 17, 2002.
1. The discrepancies we identify between the Integrated Summary and
supporting chapters appear in the October 2001 reassessment documents
that EPA distributed for internal agency review. We identified them
primarily to inform readers of our report of the source of the
information we cite. For example, a reader of the Integrated Summary
would find (outdated) information on 9 food types, whereas we are
citing information on 10 food types that is provided in the supporting
chapters of EPA's reassessment documents and that EPA officials told
us is correct.
2. Throughout the section of our report on EPA's estimate of dietary
exposure to dioxins, we attribute the identification of the
limitations to EPA's draft reassessment report.
3. Our report did not characterize the significance of the limitations
EPA identified in its reassessment documents. We have added to the
report EPA's opinion that these limitations do not represent major
weaknesses in its estimates of dietary exposure to dioxins.
4. The statement in our report that the available studies generally
were not designed to estimate national exposures is derived from page
76 of EPA's October 2001 Integrated Summary draft. In this document
EPA says: "The amount and representativeness of the data vary, but in
general these data were derived from studies that were not designed to
estimate national background means." In its written comments, EPA says
that most of the dietary exposure it estimated was derived from
studies specifically designed to estimate national exposures. In
support of this point, EPA says that 66 percent of the estimated
exposure to dioxins is from eating beef, pork, poultry, milk, and
dairy products, and that these studies were designed to estimate
national exposures. (We note that these studies cover 5 of the 10 food
types on which EPA based its exposure estimates.) Importantly, our
draft report stated that the studies on beef, pork, and poultry were
based on the first statistically designed national surveys of dioxin
levels in these foods and that the milk samples upon which both the
milk and dairy estimates were based came from a national survey with
samples collected from sampling stations in a majority of the states.
However, while our review of EPA's milk survey design plan indicated
the milk samples were intended to assess the levels of dioxins in the
general milk supply of the United States, the survey design document
also stated that (1) the milk would be collected from dairy plants
around the United States that represent approximately 20 percent of
the nation's milk supply and (2) the survey was not designed to be
statistically rigorous”that is, it was not intended to randomly sample
milk in such a way that the results could be generalized to the full
milk supply with a known degree of precision. Thus, we concluded that
EPA's statement in the Integrated Summary”that the studies covering
the 10 food types generally were not designed to estimate national
exposures”was accurate. In light of EPA's comments and the fact that
the milk samples used to estimate milk and dairy exposures did have
national coverage, we have revised the report to indicate that EPA
acknowledges that some of the available studies were not designed to
estimate national average exposures.
5. We revised the description of the fat samples from "inedible fat
samples" to cuts of fat, such as back fat on cattle, that generally
are not consumed by the U.S. public.
6. We understand that there is variability associated with
measurements at the picogram level. Nonetheless, we continue to
believe that the variability identified among the five samples studied
indicates that using fat samples not consumed by the public may
overstate or understate to some extent dioxin levels in beef, pork,
and poultry products sold to the public.
7. In its comments, EPA stated that it believes that sufficient
information is available to support a conclusion that, in spite of the
emission reduction of the late 1990s, the exposure estimates of the
draft reassessment are a reasonable characterization of contemporary
exposure. We have revised the report to include EPA's opinion and the
reasons it cited in support of its view that the emission reduction in
the late 1990s does not significantly affect the current estimate of
general population exposure. However, because EPA does not have data
on dioxin emissions after 1995, we cannot evaluate EPA's conclusion.
8. EPA stated that it plans to delete information on the variability
in dairy concentration data from the reassessment report, and we have
therefore deleted this point from our report.
9. We understand that the contamination of the two samples eliminated
from EPA's estimate was found to stem from a localized ball clay
contamination. However, we continue to believe that because of the
lack of information on the incidence of dioxin contamination in animal
feeds as well as on the potential sources of such contamination, it is
not clear that the poultry samples with high concentrations of dioxins
were anomalies. For example, this animal feed contamination problem
was identified as a result of the first national survey of only 80
poultry fat samples. We acknowledge that a decision to exclude
apparently anomalous information entails professional judgment.
However, because the incidence of contamination of animal feed is
unknown, we believe that it is important for users of the dioxin
reassessment to understand the judgments EPA made in estimating
dietary exposure.
10. In the draft report, EPA does not provide information on the
assumptions and analyses used to estimate the average fat percentages
for pork and poultry. However, EPA does provide some information on
how it estimated the fat percentage for beef. The fat percentage
estimates affect the exposure estimates, and we believe this
information should be included in the reassessment report. In its
comments to us, EPA stated that the agency is considering adding
information about the pork and poultry estimates to the report. We are
therefore deleting references to this point in our report.
11. We deleted the phrase "assembled by EPA" to be consistent with
information we provide in the body of the report that the peer review
panelists were selected by an independent contractor.
12. We have revised this statement to reflect the fact that most
(rather than all) of the other dioxins have TEFs of 0.1 or lower.
13. We clarified that TEFs apply to all effects, not just those for
which relative potency data were available.
[End of section]
Appendix VI: GAO Contacts and Staff Acknowledgments:
GAO Contacts:
David G. Wood, (202) 512-3841:
Christine Fishkin, (202) 512-6895:
Staff Acknowledgments:
Other key contributors to this report include Timothy Bober, Greg
Carroll, Nancy Crothers, Greg Wilmoth, and Carrie Wheeler.
[End of section]
Footnotes:
[1] In this report, unless otherwise indicated, we use the term
"dioxins" to refer to the three closely related families of chemical
compounds (dioxins, furans, and polychlorinated biphenyls) that EPA
evaluates in its reassessment of dioxins. In the scientific
literature, these compounds may be referred to as "dioxins and dioxin-
like compounds."
[2] The National Academies consist of four organizations: the National
Academy of Sciences, the National Academy of Engineering, the
Institute of Medicine, and the National Research Council.
[3] The September 2000 draft reassessment report is posted on EPA's
Web page. While the October 2001 draft reflects a number of revisions
to the September 2000 version on the Web page in response to public
and peer review comments, the drafts are substantially the same.
[4] The World Health Organization (WHO) met in Stockholm in June 1997
to update earlier TEFs on dioxins for human risk assessment. As of
2002, both EPA and WHO use the TEFs adopted by WHO in 1997, and
published by Van den Berg et al. in 1998.
[5] The full title of part III is Integrated Summary and Risk
Characterization for 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and
Related Compounds.
[6] The International Programme on Chemical Safety, established in
1980, is a joint program of three cooperating organizations: the
United Nations Environment Programme, the International Labour
Organisation, and WHO. The International Programme on Chemical
Safety's main roles are to establish the scientific basis for safe use
of chemicals and to strengthen national capabilities and capacities
for chemical safety.
[7] The Food and Agriculture Organization of the United Nations was
founded in 1945 with responsibilities covering nutrition and
associated international food standards. Among its activities, the
Organization approves international standards and helps frame
international conventions and agreements.
[8] EPA's Integrated Summary (table 4-7) presents information on
exposures to 9 foods, while the detailed exposure chapters, chapters 3
and 4, present information on 10 foods. However, the estimated total
exposures from foods in both parts of the reassessment are almost
identical.
[9] The reassessment report addresses variability in general
population exposure, indicating it results primarily from differences
in dietary choices that individuals make. EPA estimates that dietary
intake of dioxins for the general population may extend to levels two
to three times higher than the mean estimate.
[10] EPA does not have information on dioxin emissions reductions post-
1995. However, EPA's air toxics regulations are expected to result in
further reductions. For example, EPA expects that its 1995 air toxics
rule for large municipal waste combustors”associated with more than 60
percent of total dioxin emissions”and its 2000 air toxics rule for
small municipal waste combustors will reduce dioxin emissions from
these entities to less than 1 percent of 1990 levels.
[11] Some of the market basket surveys cited by EPA were conducted
under the auspices of the Food and Drug Administration.
[12] The report's references to this category of food are limited to
several tables in the chapters on dietary exposure in which the
estimates are provided, while the Integrated Summary cites nine foods,
excluding other meats.
[13] U.S. Environmental Protection Agency, Matthew Lorber et al,
Distribution of Dioxins, Furans, and Coplanar PCBs in Different Fat
Matrices in Cattle (Washington, D.C., 1997).
[14] EPA also excluded other beef samples from its analysis on the
basis that the source animals had unusually high levels of dioxin
exposure. However, the analysis does not explain why the ratios (and
thus the overall comparability) would vary with levels of exposure.
[15] U.S. General Accounting Office, Food Safety: Agencies' Handling
of a Dioxin Incident Caused Hardships for Some Producers and
Processors, [hyperlink, http://www.gao.gov/products/GAO/RCED-98-104],
Washington, D.C.: Apr. 10, 1998).
[16] EPA's National Bioaccumulation Study, published in 1992,
investigated the prevalence of selected bioaccumulative pollutants,
including dioxins, in fish.
[17] EPA's Environmental Radiation Ambient Monitoring System is a
national network of monitoring stations that regularly collect air,
water, precipitation, and milk samples for analysis of radioactivity.
The samples were collected from 51 stations located in 41 states,
Puerto Rico, and Panama.
[18] For beef, pork, poultry, milk, and dairy products, the toxic
concentrations are also based on EPA's estimates of the average
percentage of fat in these foods--17, 19, 9, 1.8, and
12 percent, respectively.
[19] EPA's August 1997 Exposure Factors Handbook provides data on
standard factors needed to calculate human exposure to toxic
chemicals, including the estimated average daily intake of foods that
EPA program offices are encouraged to use in exposure assessment
activities.
[20] Because the results of this expert meeting were not published
until 1998, EPA refers to this international consensus scheme as the
TEQ-WHO. update. See Martin Van den Berg, et al., "Toxic Equivalency
Factors (TEFs) for PCBs, PCDDs, PCDFs for Humans and Wildlife,"
Environmental Health Perspectives (1998): Vol. 106, No. 12: 775-792.)
[21] See U.S. General Accounting Office, Chemical Risk Assessment:
Selected Federal Agencies' Procedures, Assumptions, and Policies,
[hyperlink, http://www.gao.gov/products/GAO-01-810] (Washington, D.C.:
Aug. 6, 2001) for a more detailed description of the four-step process
and other chemical risk assessment procedures that may be used by EPA.
[22] See U.S. General Accounting Office, Environmental Protection
Agency: Use of Precautionary Assumptions in Health Risk Assessments
and Benefits Estimates, [hyperlink,
http://www.gao.gov/products/GAO-01-55] (Washington, D.C.: Oct. 16,
2000) and [hyperlink, http://www.gao.gov/products/GAO-01-810].
[23] EPA experts participated in all of these international meetings
and evaluations convened by WHO on dioxins.
[24] Group 1 is the classification for chemical agents or mixtures
that WHO's reviewers determine are carcinogenic to humans. Group 2A is
the classification for those probably carcinogenic, and Group 2B for
those possibly carcinogenic. Group 3 includes those not classifiable
as to human carcinogenicity, and Group 4 covers those probably not
carcinogenic.
[25] EPA's reassessment also noted that there is a broad range in the
quality and quantity of data available for individual dioxins.
However, EPA pointed out that five dioxins (including TCDD) contribute
approximately 80 percent of the total toxic equivalence of dioxin in
humans and characterized these five chemicals as "well studied."
Nevertheless, EPA's reassessment relied primarily on TCDD studies.
[26] The National Toxicology Program of the Department of Health and
Human Services also listed TCDD as a known human carcinogen in the
2001 addendum to its Report on Carcinogens (9th edition) on the basis
of a similar combination of epidemiological (human) and mechanistic
information, supported by experimental animal studies.
[27] EPA's risk assessment guidelines set forth "default" assumptions”
generic approaches based on general scientific knowledge and policy
judgment that are applied to various elements of the risk assessment
process when specific scientific information is not available.
[28] Although the experts participating in WHO's 1998 consultation
established a tolerable daily intake range of 1 to 4 picograms per
kilogram of body weight, they also stressed that the ultimate goal
should be to reduce human intake levels below that range and
recommended that every effort should be made to reduce exposure to the
lowest possible level.
[29] The Agency for Toxic Substances and Disease Registry in the
Department of Health and Human Services uses a similar measure known
as the minimal risk level. Minimal risk levels are estimates of the
daily human exposure to a hazardous substance that are likely to be
without appreciable risk of adverse noncancer health effects over a
specified duration of exposure. These substance-specific estimates are
intended to serve as screening levels to identify contaminants and
potential health effects that may be of concern at hazardous waste
sites. In 1999, the Agency for Toxic Substances and Disease Registry
set a minimal risk level for dioxins and related compounds of 1.0
picogram TEQ per kilogram of body weight per day, but did not use body
burden as a dose metric.
[30] Background exposure to chemicals is the exposure that regularly
occurs to members of the general population from media such as food,
air, and soil that have concentrations of these chemicals within
normal background range.
[31] WHO's IARC working groups may do some quantitative evaluations of
human data in the monographs, but without extrapolation beyond the
range of data available. Quantitative extrapolation of cancer risks
from experimental (animal) data to the human situation is not
undertaken.
[32] EPA's Science Advisory Board reviews key scientific studies and
methodologies used by the agency in formulating rules to protect the
environment and public health. The Board comprises nongovernment
experts and provides technical advice directly to the EPA
administrator primarily on the basis of its peer reviews”that is,
critical evaluations by panels of independent experts.
[33] Dose-response modeling is used to estimate the health risks
associated with various exposure levels (dose).
[34] A cancer slope factor is an upper bound estimate of the increased
cancer risk from a lifetime of exposure to an agent, generally
approximating or exceeding the 95 percent confidence limit. This
estimate is generally reserved for use in the low-dose region of the
dose-response relationship.
[End of section]
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