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A Summary of Dioxin Reports,
Assessments, and Regulatory Activity
This chapter begins with a brief summary of evaluations from several gov-
ernmental bodies on the toxicity of chlorinated dibenzo-p-dioxins (CDDs) and
related compounds, including chlorodibenzofurans (CDFs) and polychlorinated
biphenyls (PCBs) with dioxin-like activity, and on the potential human health
effects from exposure to these compounds. For brevity, these compounds will be
referred to in this report collectively as "dioxin-like compounds" (DLCs), except
when there is a need to refer to one of the specific compounds. This chapter also
contains information on DLC-related regulations and guidelines that have been
established in the United States, a number of European countries, Japan, and
Australia for the environment, feeds, and foods. The chapter concludes with
discussions on DLC monitoring and research programs and on methods of chemi-
cal analysis for DLCs in feeds and foods.
EVALUATIONS BY GOVERNMENTAL BODIES
This section presents information about the toxicity of DLCs. For CDDs and
CDFs, dioxin-like activity requires chlorination of the parent compounds at the 2,
3, 7, and 8 positions; for PCBs, this activity requires chlorination at four or more
positions (with at most one ortho substitution). While there are 75, 135, and 209
different CDDs, CDFs, and PCBs, respectively, only 7, 10, and 12 of them are
considered to have dioxin-like activity (Figure 2-1~.
This section begins with a description of toxicity equivalency factors and
toxic equivalencies, which are systems that have been developed to compare the
potential toxicities of various dioxin congeners (i.e., compounds that have similar
17
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scientific committee
18
(A)
Cl5,~~
A SUMMARY OF DIOXIN REPORTS, ASSESSMENTS, AND REGU~TORYACTIVITY 19
.
.
.
.
.
.
The Agency for Toxic Substances and Disease Registry's (ATSDR) Toxi-
cological Profile for Chlorinated Dibenzo-p-dioxins (ATSDR, 1998~.
This report primarily covers the toxicity of CDDs. It alludes to CDFs and
PCBs generally only in discussions of contaminant concentrations in
environmental media and foods since these compounds (particularly
CDDs and CDFs) are commonly analyzed simultaneously. (ATSDR has
published separate toxicological profiles on CDFs and PCBs [ATSDR
1994, 20001.)
A report prepared for the European Commission DO Environment, Evalu-
ation of the Occurrence of PCDD/PCDF and POPs in Wastes and Their
Potential to Enter the Foodchain (Fiedler et al., 2000~. This report pro-
vides a cursory discussion of toxicity, body burdens, and intakes and
focuses on the occurrence of persistent organic pollutants (POPs) in envi-
ronmental media, animal feeds, and pathways of contamination. It ad-
dresses only about a dozen POPs, but CDDs and CDFs are discussed
thoroughly because of the relatively large databases for these compounds.
A report prepared for the European Commission DO Environment and
the U.K. Department of the Environment and Transport and the Regions,
Compilation of EU Dioxin Exposure and Health Data (AEA Technol-
ogy, 1999~. This report contains a thorough review of exposure and health
effects data.
An initial report and an update from the Scientific Committee on Food of
the European Commission, Health and Consumer Protection Directorate-
General, Opinion of the Scientific Committee on Food on the RiskAssess-
ment of Dioxins and Dioxin-like PCBs in Food (Scientific Committee on
Food, 2000, 2001~. The initial report focuses on dietary exposure and
toxicity of DLCs; it does not address pathways of contamination. The
update, based on scientific information made available after release of the
initial report, includes new toxicity and tolerable intake information only.
The International Agency for Research on Cancer's (IARC) IARC Mono-
graphs on the Evaluation of Carcinogenic Risks to Humans. Volume 69:
Polychlorinated Dibenzo-para-dioxins and Polychlorinated Dibenzo-
furans (IARC, 1997~. The focus of this report is assessment of the poten-
tial human carcinogenicity of CDDs and CDFs, but other issues, such as
other types of toxicity, environmental occurrence, and human exposure,
are also covered.
The U.S. Environmental Protection Agency's (EPA) draft Exposure and
Human Health Reassessment of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin
(TCDD) and Related Compounds (EPA, 2000~. This draft reassessment
is the most extensive compilation of data on the environmental occur-
rence and toxicity of DLCs and the consequent human exposures and
risks.
20
DIOXINS AND DIOXIN-LIKE COMPOUNDS IN THE FOOD SUPPLY
Toxicity Equivalents and Toxicity Equivalency Factors
The biological activities of DLCs vary and, since humans are usually ex-
posed to mixtures of DLCs, the toxicity of an exposure depends on the particular
composition of the mixture. It is desirable to express the expected biological
activity of mixtures using a common metric. The biological activities of the
various dioxin congeners are compared to the activity of 2,3,7,8-tetrachloro-
dibenzo-p-dioxin (TCDD). TCDD is the most biologically potent of the DLCs,
and the greatest amount of toxicity information has been gathered for this dioxin
congener. The toxic potency of a mixture of DLCs is therefore expressed in
TCDD toxicity equivalents, or TEQs. As an example, exposure to a mixture of
DLCs with a potency of 2 ng TEQ/kg means that the total mixture is expected to
have the potency of an exposure equal to 2 ng TCDD/kg. The TEQ value for a
mixture is calculated by multiplying the mass or concentration of each DLC by a
toxicity equivalency factor (TEF) and summing across all DLCs present. TEFs
are calculated as a way to express the activity of DLCs in relation to TCDD as
determined by various biochemical or toxicological assays. A sample TEQ calcu-
lation is shown in Table 2-1. (For further discussion of the derivation and use of
TEQs and TEFs see EPA, 2000.)
Any mixture that yields a certain TEQ concentration is assumed to have the
same toxic potential as another mixture with the same TEQ. Although the TEF
system is useful for determining toxicity in mixtures of DLC congeners, it cannot
be used to simplify environmental fate and transport analyses of DLCs because
individual congeners differ in their physical and chemical properties, an impor-
tant consideration in fate modeling. Several TEF schemes have been developed
over the years; they differ regarding the inclusion of dioxin-like PCBs and TEFs
TABLE 2-1 Sample Toxicity Equivalents (TEQ) Calculation for a Mixture of
Dioxin-like Compounds
Compound
Mass
Concentration
(ng/kg)
Toxicity
Equivalency
Factor
TEQ
Concentration
(ng TEQ/kg)
TCDD 2 1 2
1,2,3,4,7,8-HxCDD 35 0.1 3.5
1,2,3,4,6,7,8,9-OCDF 12 0.001 0.012
3,3',4,4',5-penta-CB (PCB-126) 46 0.1 4.6
2,3,4,4',5-penta-CB (PCB-114) 186 0.0005 0.093
Total 281 10.205
NOTE: TCDD = 2,3,7,8-tetrachlorodibenzo-p-dioxin, HxCDD = hexachlorodibenzo-p-dioxin, OCDF
= octachlorodibenzofuran, CB = chlorinated biphenyl, PCB = polychlorinated biphenyl.
A SUMMARY OF DIOXIN REPORTS, ASSESSMENTS, AND REGU~TORYACTIVITY 21
for certain compounds. The biological activity of a mixture of DLCs may be
estimated differently depending on the TEF system used and the particular com-
pounds analyzed. Appendix Tables A-1 and A-2 present the common TEF sys-
tems.
Although the use of TEFs provides a convenient method for assessing the
toxicity of mixtures of DLCs, there are limitations to this method. These limita-
tions include uncertainties associated with the TEF values assigned to each DLC
congener; whether TEF values are constant across all responses and ranges of
dose; whether all effects of DLCs, including TCDD and PCB congeners, are
mediated via the arylhydrocarbon receptor; whether a TEQ for a DLC mixture is
the sum of the toxicity of each DLC present in mixture; and whether all mixtures
with the same TEQ have the same toxicity.
Potential Human Health Effects from Exposure to DLCs
Chemical dose is typically measured as an intake in units of mass per unit of
body weight, such as 2 mg of calcium/kg. However, for compounds that are
cleared slowly from the body, such as DLCs, intakes are not very useful for
understanding toxicity profiles, dose-response modeling, or interspecies com-
parisons. In the case of DLCs, a given intake can create very different internal
concentrations in the species and target organs of interest, depending on the
duration of dosing and toxicokinetic and toxicodynamic parameters (e.g., the fat
content of the target tissue and the half-life of the specific dioxin congener in an
organism). Reviews of DLC toxicity generally refer to an internal exposure met-
ric, such as body burden, or to concentration in a particular tissue when such data
are available. Different body burden definitions may be used, such as steady
state, lifetime average, or peak concentrations. Because DLCs are preferentially
associated with lipids, body burden concentrations are frequently given in units
of mass per mass of lipid. Various reports cited in this chapter provide different
measurement units. No conversions to other units were made for any of these
values to ensure the accuracy of the values as presented by the study author.
Effects Observed in Humans at General Exposures
General exposure is defined here as that received through everyday life. The
general population, breastfeeding infants, and consumers of contaminated fish
are considered to have general exposures to DLCs. Occupationally exposed work-
ers and victims of unintentional releases are not included. An exception is made
for the Times Beach, Missouri investigations, since body burdens of TCDD in
exposed subjects were similar to those of the general population, despite wide-
spread soil contamination.
The reports cited earlier (AEA Technology, 1999; ATSDR, 1998; EPA,
2000; Fiedler et al., 2000; IARC, 1997; Scientific Committee on Food, 2000,
22
DIOXINS AND DIOXIN-LIKE COMPOUNDS IN THE FOOD SUPPLY
2001) consider all human data, regardless of dose, or focus on high-dose popula-
tions because of the greater probability of observing an effect. These reports
describe certain populations as "poisoned" or "highly exposed," including those
in pesticide manufacturing studies, the Ranch Hand studies, the Seveso reports,
and the Yusho and Yu-cheng investigations (see below). There are several stud-
ies of cancer in pesticide applicators, but they are confounded by lack of specific
exposure information. Studies of Swedish (Axelson and Sundell, 1974, as cited in
EPA, 2000) and Finnish (Riihimaki et al., 1982, 1983, as cited in EPA, 2000)
applicators that used both 2,4-D (2,4-dichlorophenoxyacetic acid) and 2,4,5-T
(2,4,5-trichlorophenoxyacetic acid) showed a slight increase in relative risk for
cancer, but exposure to TCDD or other DLCs was not quantified.
A study of 1,261 Air Force veterans known as Ranch Hands, who were
responsible for aerial herbicide spraying in Vietnam, showed that the men had a
median TCDD blood serum level that was 12.4 ppt (range 0-618 ppt) compared
with 4.2 ppt in controls (Air Force veterans engaged in cargo transport), with the
greatest exposure in the nonflying ground personnel (median value 23.6 ppt)
(Wolfe et al., 1990, as cited in EPA, 2000~. Follow-up studies through the early
l990s suggested that this group did not have an increased risk of cancer death,
although it was noted that in general the Ranch Hands did not have elevated
TCDD levels significantly above background and were still a relatively young
group, taking into account a 20-year cancer latency period (EPA, 2000~.
In 1976, an unintended industrial release in Seveso, Italy, exposed a large
population of people to TCDD. At the time of the release, serum levels of TCDD
were as high as 56,000 ppt for the most highly exposed children, who developed
severe chloracne (Mocarelli et al., 1991, as cited in EPA, 2000~. Twenty years
after the release, tissue plasma levels of TCDD were measured in randomly
selected residents. Those from the area with the greatest initial exposure had
geometric mean TCDD levels of 53.2 ppt (n = 7; range 1.2-89.9 ppt); those with
the next greatest exposure had 11.0 ppt (n = 51~; and those with the lowest
exposure had 4.9 ppt (n = 52) (Landi et al., 1996, 1998, as cited in EPA, 2000~. In
a 15-year follow-up, the overall cancer mortality in the residents did not appear to
be increased compared with a control group from outside the exposed area,
although significant excess mortality risks occurred in the lowest exposure group
for esophageal cancer in males and bone cancer in females (Bertazzi et al., 1997,
1998, as cited in EPA, 2000~. EPA reports that the cancer data appear to be
contradictory and are difficult to interpret because of the small number of cases,
problems with exposure classification, and a 15-year rather than a 20-year fol-
low-up (EPA, 2000~.
Two significant occurrences of poisoning of food oils with PCBs and furans
have been reported in Japan. The first occurred in 1968 in the Yusho incident, in
which 1,900 people unintentionally consumed up to 2 g of rice oil that contained
a 1:250 ratio of furans to PCBs. Tissue studies indicated that both the furans and
A SUMMARY OF DIOXIN REPORTS, ASSESSMENTS, AND REGU~TORYACTIVITY 23
the PCBs were retained for many years. There was a significantly increased risk
of liver cancer in males 15 years after the incident, although determination of rice
oil as the culprit was problematic (Kuratsune et al., 1988, as cited in EPA, 2000~.
Noncancer effects included acneform eruptions, hyperpigmentation, and hyper-
keratosis and ocular lesions. The second incident (Yu-chen) was a contamination
of cooking oil in Taiwan in 1979 that affected 2,000 people and resulted in
similar noncancer effects. Six months after the incident, blood PCB levels ranged
from 11 to 720 ppb with a mean value of 49 ppb and most values less than 100
ppb (Chen et al., 1980, as cited in EPA, 2000~.
There have been few epidemiological investigations of the health effects of
DLCs in populations with no extraordinary exposure circumstances. A large
population of children from an industrial region in the Netherlands is currently
being studied for a variety of health outcomes in relation to exposure to DLCs
(Vreugdenhil et al., 2002), and Koopman-Esseboom and colleagues (1994a) ex-
amined DLC levels in blood and human milk in two cohorts, one industrial and
one rural, in the Netherlands (see below).
Cancer. Epidemiological studies on carcinogenicity from general exposures
to DLCs are sparse, but experimental animal studies provide strong support of
carcinogenicity. The IARC monographs (1997) include no cancer epidemiology
studies regarding general exposures to CDDs and express no opinion about the
potential for carcinogenicity from such exposures. All of the investigations de-
scribed in the monographs are cohort studies of workers with known, inferred, or
presumed exposure to CDDs (usually TCDD); cohort studies of the Seveso popu-
lation with unintentional TCDD exposure; or case-control studies in which sub-
jects had known or expected contact, usually on the basis of occupation, with
chlorophenoxy herbicides that likely contained TCDD. The monograph on CDFs
describes a few studies of cancer in humans, including investigations that showed
a moderate increase in cancer incidence and mortality in Swedish fishermen and
consumers of Baltic Sea fish. Stomach cancer incidences in the Swedish consum-
ers were 2.2 (1.3-3.5) and 1.6 (1.0-2.4) per thousand, compared with consumers
of Atlantic Ocean fish and regional referents, respectively. Squamous-cell skin
cancer rates were 1.9 (1.2-3.1) and 2.3 (1.5-3.5) per thousand compared with
Atlantic Ocean fish consumers and the referent group, respectively (IARC,1997~.
EPA (2000) includes no cancer epidemiology studies regarding general ex-
posures to DLCs, but it does provide dose-response data for populations that are
highly exposed to DLCs. The relative risk for total cancer for the lowest-exposed
stratum in the epidemiological studies cited by EPA ranged from 0.9 to 1.24 (see
Appendix Table A-3~. However, as reported by EPA (2000), in some exposed
populations such as those in Seveso, Italy, the calculated relative risk for specific
cancers was considerably higher (e.g., the relative risk for connective and soft
tissue sarcoma in males was 2.8~. In studies that have identified specific cancers
24
DIOXINS AND DIOXIN-LIKE COMPOUNDS IN THE FOOD SUPPLY
arising after DLC exposure, the evidence is equivocal. However, the cumulative
evidence of all studies is consistent with the possibility that DLC exposure is
. .
carclnogemc.
None of the evaluations reviewed by the committee (AEA Technology, 1999;
ATSDR, 1998; EPA, 2000; Fiedler et al., 2000; IARC, 1997; Scientific Commit-
tee on Food, 2000, 2001) derives a conclusion about the carcinogenic potential of
DLCs to humans solely from general exposures.
Noncancer Effects. Several potential noncancer health effects from general
exposures to DLCs have been reported in recent evaluations of DLC toxicity
(ATSDR, 1998; EPA, 2000; Fiedler et al., 2000; IARC,1997~. These evaluations
indicate that there are possible adverse neurobehavioral effects and changes in
the distribution of thyroid hormone concentrations in breastfed infants compared
with formula-fed infants. Koopman-Esseboom and colleagues (1994b) found a
negative correlation between extended DLC exposure and thyroid hormone lev-
els in infants and mothers. The Scientific Committee on Food (2000, 2001) also
reports neurobehavioral effects and changes in thyroid hormone status in breastfed
infants, but stated that these adverse effects were "subtle, within the normal
range, and considered without clinical relevance," whereas Weisglas-Kuperus
and coworkers (2000) and Patandin and coworkers (1998) concluded that DLCs
have a negative effect on neurodevelopment, birth weight, and immunity. EPA
(2000) identifies one study that found changes in the distribution of alanine
aminotransferase and aspartate aminotransferase concentrations in breastfed in-
fants.
Adverse effects on infant birth weight, neurodevelopment, neurobehavior,
thyroid hormone status, and the immune system in children have been reported
(AEA Technology, l999~. These observations were made in infants in the general
population and in children whose mothers ate DLC-contaminated fish from Lake
Michigan. Neurodevelopmental delays in breastfed infants in a Dutch study were
also reported (Huisman et al., 1995~. A negative correlation was found between
neurodevelopment in infants and breast-milk concentrations of PCBs. At 42
months of age, the cognitive decrement remained (Patandin et al., 1999), al-
though the psychomotor deficits seen at younger ages had disappeared (Lanting
et al., 1998~. A study of early learning in school-age Dutch children found that
prenatal exposures to DLCs resulted in impaired cognitive and motor abilities,
which could persist when the home environment was less than optimal, but no
long-term impairment could be measured in children raised in more optimal
environments (Vreugdenhil et al., 2002~. One evaluation (AEA Technology,
1999) notes that people with exposure to TCDD from the Times Beach contami-
nation showed reduced immune response and changes in T-lymphocyte differen-
tiation, and people eating relatively large amounts of Baltic Sea fish showed
changes in T-cell lymphocytes, but IARC (1997) reports contradictory findings
about cell-mediated immunity in the Times Beach subjects. EPA (2000) consid-
A SUMMARY OF DIOXIN REPORTS, ASSESSMENTS, AND REGU~TORYACTIVITY 25
ers the data about immunological effects from exposures to DLCs to be inconclu-
sive.
Effects Observed in Humans at Higher Exposures
Cancer. The IARC (1997) evaluation discusses the body of epidemiological
literature on CDDs, but it focuses on the high-exposure cohorts with documented
TCDD exposure (all occupational exposures) in its evaluation of whether CDDs
are carcinogenic to humans. It concludes that the overall standardized mortality
rate for all cancer types combined was 1.4 per thousand (95 percent confidence
interval, 1.2-1.6) for the most highly exposed subgroups in these occupational
cohorts; statistically significant dose-response trends in two of the studies
strengthen that opinion.
IARC also concludes, however, that the epidemiological data provide "lim-
ited evidence" of a carcinogenic effect of TCDD in humans, although the IARC
monographs (1997) upgrade 2,3,7,8-TCDD from classification 2A, Probably
Carcinogenic to Humans, to 1, Carcinogenic to Humans. In its monograph on the
carcinogenicity of CDFs, IARC notes that male victims of the Yusho incident had
a threefold excess of liver cancer mortality, but that no such excess occurred in
victims of the Yu-cheng incident, and finds the evidence for the carcinogenicity
of CDFs in humans to be inadequate.
The reports of the Scientific Committee on Food (2000,2001) rely largely on
the IARC (1997) evaluation and state that TCDD should be regarded as a human
carcinogen, though not a direct-acting genotoxin. The report prepared by Fiedler
and colleagues (2000) repeats the IARC (1997) evaluation of the carcinogenicity
of CDDs. AEA Technology (1999) concludes that the epidemiological data sug-
gest that TCDD exposure increases the rates of all cancers. On the basis of the
epidemiological and animal studies, ATSDR (1998) concludes that TCDD may
be a human carcinogen.
EPA (2000) considers TCDD to be a human carcinogen and that other DLCs
are likely to be human carcinogens, based on a combination of epidemiological
and animal cancer studies and mechanistic information. The epidemiological data
alone do not demonstrate a causal association between exposure and cancer, but
suggest that the compounds are multisite carcinogens, increasing cancer at all
sites, lung cancer, and perhaps other particular cancers. EPA (2000) describes
TCDD as a nongenotoxic carcinogen and a potent promoter.
Noncancer Effects. A number of noncancer human health effects have been
associated with high exposures to DLCs. These effects are listed below.
.
Chloracne and other dermal effects (ATSDR, 1998; EPA, 2000; Fiedler
et al., 2000; IARC, 1997~.
26
Estimates of Tolerable Intakes
DIOXINS AND DIOXIN-LIKE COMPOUNDS IN THE FOOD SUPPLY
Changes (AEA Technology, 1999; ATSDR, 1998; Fiedler et al., 2000;
IARC, 1997) or possible changes (EPA, 2000; Scientific Committee on
Food, 2000, 2001) in glucose metabolism and in diabetes risk.
Alterations (ATSDR, 1998) or possible alterations (EPA, 2000) in thy-
roid function.
Alterations in growth and development (AEA Technology, 1999; IARC,
1997; Scientific Committee on Food, 2000, 2001), neurodevelopment
(AEA Technology, 1999; IARC, 1997), and neurobehavior (AEA Tech-
nology, 1999; IARC, 1997; Scientific Committee on Food, 2000, 2001~.
EPA (2000) considers postnatal developmental effects on neurobehavior
to be possibly related to exposures to DLCs. Fiedler and colleagues (2000)
note that there was an altered sex ratio among births after the Seveso
unintended exposure.
Increased gamma-glutamyl transferase concentrations (EPA, 2000; Sci-
entific Committee on Food, 2000, 2001~.
Altered concentrations of reproductive hormones in men (EPA, 2000~.
Alterations in liver function (Fiedler et al., 2000; IARC, 1997) and he-
patic effects (ATSDR, 1998~.
Possibly altered serum lipid (EPA, 2000; Scientific Committee on Food,
2000, 2001) and cholesterol concentrations (EPA, 2000~.
Possibly altered alanine aminotransferase and aspartate aminotransferase
concentrations (EPA, 2000~.
Alterations in the immune system (Fiedler et al., 2000; IARC, 1997~.
Possible ocular changes (ATSDR, 1998; IARC, 1997~.
Increased mortality from cardiovascular disease (AEA Technology, 1999;
Scientific Committee on Food, 2000, 2001~.
Toxicity Benchmarks
Several governmental bodies have derived or recommended acceptable daily
intakes or similar parameters for TCDD or DLCs as a group (AEA Technology,
1999; ATSDR, 1998; EPA, 2000; Fiedler et al., 2000; Scientific Committee on
Food, 2000, 2001~. These guidance levels are summarized in Table 2-2.
ATSDR (1997) defines a minimal risk level (MRL) for a hazardous sub-
stance (e.g., DLCs) as an estimate of daily human exposure that is likely to be
without appreciable risk of adverse noncancer health effects over a specified
duration and route of exposure. For 2,3,7,8-TCDD, ATSDR (1998) derives MRLs
for oral exposure to over three intervals: acute (14 days or less), intermediate
(15-364 days), and chronic (1 year or more). An MRL is "an estimate of the daily
human exposure to a hazardous substance that is likely to be without appreciable
risk of adverse non-cancer health effects over a specified duration of exposure"
A SUMMARY OF DIOXIN REPORTS, ASSESSMENTS, AND REGULATORYACTIVITY
TABLE 2-2 Estimates of Tolerable Intakes of Dioxins and Dioxin-like
Compounds
Reference Cancer Noncancer
ATSDR, 1998 None given Acute oral MRL:
200 pa/kg/d (TCDD)
Intermediate oral MRL:
20 pa/kg/d (TCDD)
Chronic oral MRL:
1 pa/kg/d (TCDD)
EPA, 2000 1 x 10-3 pa/kg/d (TCDD) None given
or
0.001 pa/kg/d at a 1 in
1 million excess risk level
Scientific Committee on
Food, 2000, 2001
AEA Technology, 1999;
Fiedler et al., 2000
14 pg TEQ DFp wHog8lkglwk
1-4 pg TEQ/kg/d (CDDs, CDFs, PCBs)
NOTE: MRL = minimal risk level, TCDD = 2,3,7,8-tetrachlorodibenzo-p-dioxin, TEQ = toxicity
equivalents, CDD = chlorinated dibenzo-p-dioxin, CDF = chlorodibenzofuran, PCB = polychlori-
nated biphenyl.
(ATSDR, 1998~; the MRL does not pertain to cancer. The MRLs for TCDD are,
respectively, 0.0002 ,ug/kg/d (200 pg/kg/d), 0.00002 ,ug/kg/d (20 pg/kg/d), and
0.000001,ug/kg/d (1 pg/kg/d). The acute MRL is based on immunological effects
in female mice, the intermediate MRL on immunological effects in guinea pigs,
and the chronic MRL on developmental effects in rhesus monkeys. In each case,
uncertainty factors are applied to address animal-to-human extrapolation, inter-
individual variation in response, and (if necessary) a low-effect to no-effect dose
extrapolation.
The report by Fiedler and colleagues (2000) reiterates the World Health
Organization (WHO)-recommended tolerable daily intake (TDI) of DLCs of 1 to
4 pg TEQ/kg/d and also WHO's recommendation that exposures should be re-
duced as much as possible. Similarly, the AEA Technology (1999) report encour-
ages member states of the European Union to adopt the recent WHO recommen-
dation, and notes that PCBs contribute about half of dietary TEQ exposure. The
Scientific Committee on Food (2000, 2001) derived a tolerable weekly intake
(TWI) of DLCs based on TCDD body burdens associated with sensitive effects in
experimental animals: developmental and reproductive effects in rats and mon-
keys and endometriosis in monkeys. Body burdens associated with the lowest-
observed-adverse-effect levels in the relevant studies ranged from about 30 to
100 ng TCDD/kg. The estimated human dietary intakes needed to produce these
body burdens were then calculated, and safety factors (ranging from 3 to 10) were
applied. The lowest TDI thus calculated was 2 pg TCDD/kg, corresponding to a
42
DIOXINS AND DIOXIN-LIKE COMPOUNDS IN THE FOOD SUPPLY
environmental and food monitoring programs are summarized in Appendix Tables
A- 17 and A- 18, respectively.
Environmental, Feed, and Food Monitoring. FDA currently uses a subsample
of between 200 and 300 food items from the Total Diet Study (TDS) to analyze
for DLCs. This analysis is conducted separately from the analysis in the TDS (see
Chapter 5~. The sampling is conducted once per year and has been completed up
to 2001. The food samples typically chosen are those that have not previously
been analyzed for DLCs or those that may contain animal fats.
In addition to TDS sampling, FDA conducts a targeted sampling study aimed
at foods that are potentially variable in contaminant levels, such as fish, vegetable
oils, and dietary supplements. For example, a number of different fish varieties
may be sampled rather than just one species in order to understand the sources of
DLCs and the variability across species. This sampling is conducted on a yearly
basis and generally includes 500 to 1,000 samples.
FDA also follows up on any unusually high values in any of their studies to
determine sources of DLCs in the food supply. FDA does not target any specific
imported foods, but it tries to create a representative sample of the diet of the
general U.S. population, which may include imported foods. When FDA does
investigate an imported food, it tends to look at imports from the top three
countries for that product.
USDA and EPA conducted a joint program of three surveys for DLCs in
beef, pork, and poultry, using 60 to 80 samples in each survey taken from feder-
ally inspected slaughterhouses in the United States. These studies were not re-
peated or continuous studies, but rather one-time events. Sixty-three beef samples
were collected in May and June 1994 and examined for CDDs and CDFs. The
sampling for the pork survey took place in August and September 1995 and
yielded 78 final samples. It was the first survey for CDDs and CDFs in pork in the
United States. Sampling was conducted in September and October 1996 for
poultry, with a final sample size of 80. This poultry survey was also the first of its
kind in the United States to survey for CDDs and CDFs (see later section, "Con-
centrations of DLCs in Foods".
Human Biomonitoring. The Centers for Disease Control and Prevention's
(CDC) National Health and Nutrition Examination Surveys (NHANES) are a
series of studies that have collected data on the health and nutritional status of
the U.S. population since the early 1960s. Between 1998 and 2001, the dietary
component of NHANES and the USDA/Agricultural Research Service Continu-
ing Survey of Food Intakes by Individuals merged; NHANES also became a
continuous and annual survey. The sampling plan for each year follows a com-
plex, stratified, multistage, probability cluster design to select a representative
sample (approximately 5,000 individuals) of the noninstitutionalized, civilian
U.S. population.
A SUMMARY OF DIOXIN REPORTS, ASSESSMENTS, AND REGU~TORYACTIVITY 43
The NHANES protocol includes a home interview followed by a standard-
ized physical examination in a mobile examination center. As part of the exami-
nation protocol, blood is obtained by venipuncture from participants aged 1 year
and older, and urine specimens are collected from people aged 6 years and older.
The venipuncture is performed to obtain laboratory results that provide preva-
lence estimates of disease, risk factors for examination components, and baseline
information on the health and nutritional status of the population. Recently in-
cluded among the NHANES laboratory measures are serum dioxins, furans, and
coplanar PCBs.
CDC's National Center for Environmental Health, Division of Laboratory
Sciences, performs the environmental chemical analysis of the blood or urine
specimens collected in NHANES. The first National Report on Human Exposure
to Environmental Chemicals (CDC, 2001) did not include DLC measurements.
The second national report (NCEH, 2003), using data from the 1999-2000
NHANES survey, included DLC results, along with other environmental chemi-
cal analyses; data for people older than 12 years, including major demographic
attributes (e.g., race and sex); and approximately 2,500 samples (from approxi-
mately 10,000 participants for the 2-year period, 5,000 participants per year).
Unfortunately, none of these data were available in time for inclusion in this
report. Human exposure data from the 2001-2002 NHANES survey on DLCs
(and other environmental chemicals) is estimated to be released in fall 2003. It is
anticipated that all four years of the NHANES data (1999-2002) will be com-
bined for a more refined demographic analysis; it is not known when these data
will be released.
Monitoring Programs of Other Countries and Organizations
EC. Appendix Table A-l9 summarizes the nationally funded monitoring
programs' research activities that were underway as of 1999 in each EC member
state. Programs that were completed by 1999 are not included in this list.
Currently, there are several additional on-going DLC surveys in the United
Kingdom, including cow's milk studies, wild and farmed fish studies, total diet
studies, and a baby food study that is about to be launched (Personal communica-
tion, M. Gem, U.K. Food Standards Agency, May 3, 2002~. Beginning in July
2002, EC member states are required to conduct food surveillance studies. In
2002, the United Kingdom will collect 62 food samples, concentrating on foods
containing fat; the number of samples will be doubled in 2003 (Personal commu-
nication, M. Gem, U.K. Food Standards Agency, May 3, 2002~. These results
will be published in Food Safety Information Sheets. Several countries, including
Austria, Belgium, Denmark, Finland, Germany, the Netherlands, Spain, Sweden,
and the United Kingdom, have also participated in the WHO assessment of DLC
concentrations in human breast milk.
44
DIOXINS AND DIOXIN-LIKE COMPOUNDS IN THE FOOD SUPPLY
WHO/FAD. WHO is involved in several monitoring studies of human breast
milk and food. Through its European Center for Environment and Health in
Bilthoven, the Netherlands, WHO conducts periodic studies on concentrations of
DLCs in human breast milk, predominately in European countries.
Since 1976, WHO has been responsible for the Global Environment Moni-
toring System's Food Contamination Monitoring and Assessment Program. This
program provides information on levels and trends of contaminants in food
through its network of participating laboratories in over 70 countries around the
world. The main objectives of the program are to collect data on levels of certain
priority chemicals (including DLCs) in foods, to provide technical coordination
with countries wanting to implement monitoring studies on foods, and to provide
information to JECFA on contaminant levels to support its work on international
standards on contaminants in foods.
Australia. DLCs are not routinely monitored in Australia, and there are very
few data on the levels of DLCs in either the environment or in food. However, a
survey of DLC levels in foods is currently being conducted by the Department of
Health and Aging, the Australia New Zealand Food Authority, and the Australian
Government Analytical Laboratories.
Japan. Japan's Law Concerning Special Measures Against Dioxins requires
that businesses conduct surveillances of DLC concentrations in emission gas,
effluent, ash, dust, and other compounds at least once a year. These results are to
be submitted to prefectural governors. Beyond the regulatory requirements, it
appears that there are not any ongoing surveillance programs in Japan (see Ap-
pendix Table A-20. However, several studies were conducted in 1998 and 1999
in order to identify DLC concentrations in blood, air/indoor air/soil, dust and
soot/water, and food. These studies include:
.
.
.
The State of Dioxin Accumulation in the Human Body, Blood, Wildlife,
and Food: Findings of the Fiscal 1998 Survey. Sponsored by the Ministry
of the Environment: Environmental Health and Safety Division, Environ-
mental Health Department, Environment Agency of Japan (cited in Tran
et al., 2002~.
Survey on the State of Dioxin Accumulation in Wildlife: Findings of the
Fiscal 1999 Survey. Sponsored by the Ministry of the Environment: En-
vironmental Risk Assessment Office, Environmental Health Department,
Environment Agency of Japan (cited in Tran et al., 2002~.
Detailed Study of Dioxin Exposure: Findings of the Fiscal 1999 Survey.
Sponsored by the Ministry of the Environment: Environmental Risk As-
sessment Office, Environmental Health Department, Environment
Agency of Japan (cited in Tran et al., 2002~.
A SUMMARY OF DIOXIN REPORTS, ASSESSMENTS, AND REGU~TORYACTIVITY 45
Canada. The Feed Program in the Canadian Food Inspection Agency (CFIA)
routinely monitors for contaminants in livestock feeds as part of their National
Feed Inspection Program. In a preliminary survey conducted by CFIA in 1998-
1999, 24 fishmeals and feeds and 9 fish oils were sampled across Canada and
tested for dioxins, furans, and PCBs. The results are summarized in Appendix
Table A-21. CFIA is currently utilizing these results to develop a continuing
monitoring plan for dioxin, furans, and PCBs and future regulatory approaches.
Research Programs in the United States
While significant academic and industrial research on DLCs exists, many
governmental organizations also have an active role in promoting and conduct-
ing research on DLCs. Much of this research is in complement to on-going
monitoring and surveillance programs and includes a variety of modeling stud-
ies to evaluate the behavior of DLCs in the air, how they move through the
environment, and how they become part of the food supply. The U.S. govern-
ment has also been conducting research into the effects of exposure to DLCs on
humans and examining historical data to determine how DLC levels change
through time. Representative federal research programs are summarized in Ap-
pendix Table A-22.
Research Programs in Other Countries and Organizations
European Commission. Appendix Table A-23 summarizes the nationally
funded research activities that were underway as of 1999 in each EC member
state. Programs that were completed by 1999 are not included in this list.
WHO/FAD. WHO is involved in several research studies. The major re-
search endeavor includes working with the United Nations Environmental Pro-
gramme to provide risk assessments of POPs, including DLCs.
Chemical Methods for Analysis of DLCs in Feeds and Foods
Not all feeds or food products have been found to be at equal risk for DLC
contamination. While commonly associated with feeds and foods containing ani-
mal fats, DLCs can, however, also be found in vegetables, fruits, and cereals. The
need for detection of DLCs at these low levels makes the current quantitative
methods of analysis expensive and challenging to perform, which limits the
number of laboratories available to conduct these tests (Hess and Stevens, 2001~.
In order to efficiently develop a reliable picture of DLCs in the food supply, both
screening methods (which can be used to analyze a large number and variety of
feed and food samples), and trace analysis (which can quantify low levels of
DLCs in follow-up to a positive screening result) can be useful.
46
DIOXINS AND DIOXIN-LIKE COMPOUNDS IN THE FOOD SUPPLY
Both current screening and trace analysis methods follow a two-part proce-
dure: extraction/separation of the sample, where the compounds of interest are
isolated from the matrix; and instrumental analysis, where DLCs are detected.
The major challenge with regard to food samples is the extraction/separation of
DLCs from other compounds in the food matrix. Techniques for DLC extraction
from fruits, hard vegetables, soft vegetables, grains, dairy products, fish, and
meats are very different, and composite foods and food additives are especially
challenging.
Screening Methods
Because of their speed and cost efficiency, significant efforts have been
made in recent years to develop screening assays for determining DLC and PCB
contamination. However, screening assays provide speed and cost savings at the
expense of specificity and a lower level of detection (Has s and Stevens, 2001~.
They do provide the sensitivity of conventional assays and, most importantly,
minimize false negatives. Although to quantify contamination levels, trace analy-
sis must follow a positive screening result, screening methods can be very useful
in detecting a contamination event or identifying critical control points in a
potential contamination pathway.
Two cost-effective approaches have been developed for screening purposes:
instrumental methods and biotechnology approaches. Both approaches rely on
the same basic extraction methods used in trace analysis, while reducing the cost
of the analytical measurement.
Of the two screening methods, the development of the CALUX method was
supported under a Small Business Innovation Research Grant from the National
Institute of Environmental Health Sciences. FDA's Center for Veterinary Medi-
cine, Arkansas Regional Laboratory, has a licensing agreement to use the CALUX
method for its DLC research.
Instrumental Methods
Instrumental methods of screening for the presence of DLCs respond to the
physical properties of the compounds. Interfering compounds that were not re-
moved during the initial extraction procedure and may cause an overestimate of
DLC contamination levels can be identified in an initial analysis. A secondary
clean-up of the sample can be performed and the sample can be reanalyzed,
reducing the number of false positives that this methodology produces.
Biotechnology Approach
The biotechnology approach is based on the chemical reactivity of com-
pounds and uses immunoassay-type tests and arylhydrocarbon receptor-type tests.
A SUMMARY OF DIOXIN REPORTS, ASSESSMENTS, AND REGU~TORYACTIVITY 47
In comparison studies, the biotechnology approach has been found routinely to
overestimate DLC content in the presence of interfering compounds, which re-
sults in false positives (Hess and Stevens, 2001~. While some interfering com-
pounds are removed during the extraction phase of the test, the residual presence
of these compounds is not detectable during a biotechnology-based assay. Even
more seriously, this approach also can have a problem with false negatives due to
analyte loss during the extraction phase (Hess and Stevens, 2001~. Assays of
duplicate aliquots from a single sample can minimize this problem, but this
doubles the cost of analysis.
Analytical Methods for Analysis of DLCs in Feeds and Foods
Trace Analysis
The analytical approach used most frequently to detect DLCs in feeds and
foods relies on isotopic dilution. This method is isomer specific, very sensitive,
and robust, although expensive and demanding. Following the extraction phase, a
known amount of the isotope i3C iS added to the sample, which creates a mixture
of forms of the compound of interest that are chemically identical, yet distin-
guishable by mass spectrometry. Using a combination of gas chromatography
and high-resolution mass spectrometry allows determination of the ratio between
each analyte and its associated isotonically labeled standard, leading to accurate
quantification of analyte concentration. The overall accuracy of the assay de-
pends on the ability to spike the sample with the isotope accurately, weigh the
sample, and measure the ratio. The effects of interfering compounds and minor
sample losses due to handling are detectable and correctable. The analytical cost
estimates associated with the standard analytical method for DLCs obtained from
a number of sources are summarized in Appendix Table A-24.
EPA-Approved Method for Analysis of Dioxins and Furans in Wastewater
In 1997, to augment less sensitive methods approved earlier, EPA Method
1613: Tetra- Through Octa-Chlorinated Dioxins and Furans by Isotope Dilution
High Resolution Gas Chromatography/High Resolution Mass Spectrometry
(HRGC/HRMS), EPA 821-B-94-005, was approved. Method 1613 is the most
sensitive analytical test procedure approved under the Clean Water Act for the
analysis of CDDs and CDFs and was developed to meet the need for more
stringent pollutant monitoring and control. Method 1613 also allows determina-
tion of the 17 terra- through octa-chlorinated, 2,3,7,8-substituted CDDs and CDFs.
Method 1613 extends minimum levels of quantitation of CDDs and CDFs
into the low parts-per-quadrillion range for aqueous matrices and the low parts-
per-trillion range for solid matrices. Furthermore, the use of isotope dilution
48
DIOXINS AND DIOXIN-LIKE COMPOUNDS IN THE FOOD SUPPLY
techniques, internal standard calibration, and the 1600 series method quality
control protocol results in improved sensitivity, precision, and accuracy. These
improvements have been validated through both intra- and interlaboratory valida-
tion studies. Method 1613 is also intended to encourage advances in technology
and reductions in the cost of analysis by allowing the use of alternate extraction
and clean-up techniques. The analyst is permitted to modify the method to over-
come interferences or to lower the cost of measurements, provided that all method
equivalency and performance criteria are met.
Concentrations of DLCs in Foods
This section presents recent data (1990 or later) regarding the concentrations
of DLCs in European and North American foods, as provided by AEA Technol-
ogy (1999), ATSDR (1998), EPA (2000), Fiedler and colleagues (2000), IARC
(1997), and the Scientific Committee on Food (2000, 2001~.
Recent Contamination Levels in Foods
Appendix Table A-25 provides DLC values for foods other than breast milk.
The data are very heterogeneous with regard to collection date, the number of
samples of a particular food, sampling method (individual versus composite
samples), the compounds analyzed, the unit of analysis (e.g., fat, fresh weight,
dry weight), and the state of the food (e.g., raw or cooked). Numbers in the table
may represent means, ranges of means, or ranges of observations.
Temporal Trends
Evidence of temporal trends in the data on DLC contamination levels in
foods is presented in some reviews, if only indirectly, in decreasing estimates of
dietary intakes of DLCs. EPA (2000) reports, specifically that:
Concentrations of dioxins and furans in U.K. cows' milk declined from
1.1 to 3.3 pg I-TEQDF/g of lipid in 1990 to 0.67 to 1.4 pg I-TEQDF/g of
lipid in 1995.
The mean pg I-TEQDF/g of lipid in German milk declined by about 25
percent between 1990 and 1994.
Examination of U.S. foods preserved over the last several decades sug-
gests that dioxin and furan concentrations were two to three times higher
in the 1950s to 1970s than at present, while PCB concentrations were ten
times higher.
IARC (1997) states that PCDD/PCDF in milk, dairy products, eggs, poultry,
and "fatty food composites" in the United Kingdom decreased markedly during
A SUMMARY OF DIOXIN REPORTS, ASSESSMENTS, AND REGU~TORYACTIVITY 49
the 1980s. Fiedler and colleagues (2000) cite a decrease in the level of contam~
nation of German foods, most markedly for dairy products, meat, and fish.
In 1998, an EPA study compared the DLC concentration in historic samples
to current DLC concentrations derived from post-1993 national food surveys for
beef, pork, poultry, and milk (Winters et al., 1998~. The surveys' principal objec-
tive was to determine the national average concentration of DLCs in the lipids of
these animal-fat products. National mean TEQ concentrations from these surveys
are shown in Appendix Table A-26.
Appendix Table A-27 presents the PCDD/PCDF and PCB TEQ concentra-
tions of the 14 historical samples, as well as TEQ concentrations normalized and
expressed as a percent of current concentrations for the most similar food type.
For example, the 1908 beef ration percentage of 38 percent means that the 0.34
pg TEQ/g of lipid PCDD/PCDF (calculated at nondetects = I/2 limit of detection)
is 38 percent of the current beef concentration of 0.89 pg TEQ/g of lipid (at
nondetects = i/: limit of detection), as determined by the recent national EPA beef
survey.
.
Although not necessarily representative of these food types or their respec-
tive time period, it should be noted that all 10 samples from 1957 to 1982 were
higher in PCDD/PCDF TEQ than the current mean concentrations (at nondetects
= i/: limit of detection), and that 12 of the 13 samples taken from 1945 through
1983 were higher for PCB TEQ. If the samples are indicative of past concentra-
tions of DLCs, normalized TEQ suggests a PCDD/PCDF concentration two to
three times higher during the period of peak environmental loading, while PCB
TEQ may have been over 10 times current concentrations. EPA plans to con-
tinue analyzing historic meat and dairy products as additional samples become
available.
Contribution of Food Groups to DLC Exposure
According to the Scientific Committee on Food (2000), the major sources of
dietary exposure to PCDD/PCDF intakes in Europe are milk and dairy products
(16 to 39 percent), meat and meat products (6 to 32 percent), and fish and fish
products (11 to 63 percent). Fish was a particularly large contributor in Finland
and Sweden, fruits and vegetables in Spain, and cereals in the United Kingdom.
In Germany, milk, meat, and fish contributed 31 percent, 23 percent, and 17
percent, respectively, of dietary I-TEQ from PCDD/PCDF (Scientific Committee
on Food, 2000~.
Temporal Trends
Several of the reviewed reports describe data that suggest a decrease in DLC
intakes over recent decades. AEA Technology (1999) reports three time trend-
so
DIOXINS AND DIOXIN-LIKE COMPOUNDS IN THE FOOD SUPPLY
analyses of DLC intake. Dutch data on DLC in foods gathered in 1978, 1984 to
1985, and 1994 indicate a statistically significant decreasing trend in adult intake
over time, with a 50 percent decrease in I-TEQ/kg/d over each 5.5-year interval in
that penod. Dietary studies conducted in Germany in 1989 and 1995 indicate a 45
percent decrease in I-TEQ intake. Diet studies in the United Kingdom in 1982,
1988, and 1992 suggest a 45 percent decrease in intake at each time point com-
pared to the preceding point. All of these estimates likely pertain to the average
consumer. Independent of changes over time in the DLC content of food and in
dietary intake, it is generally recognized that body burdens of DLCs increase with
age due, in part, to the long half-lives of these compounds.
Summary
This chapter summarizes reports on the toxicity and risk of DLCs and on
regulatory activity in the United States and other countries that are widely recog-
nized to reflect current status and knowledge of these compounds (AEA Technol-
ogy, 1999; ATSDR, 1998; EPA, 2000; Fiedler et al., 2000; IARC, 1997; Scien-
tific Committee on Food, 2000, 2001~. The risks from exposure to DLCs outlined
in these documents are based on population groups that received exposures ex-
ceeding the daily exposures estimated for the general population, so risks to the
general population are not known. Efforts to regulate DLCs range from exposure
limits and environmental emission regulations to guidelines and recommenda-
tions to limit DLC levels in feed and food. Efforts in the United States and other
countries to monitor DLCs and gather more current data are descnbed. Research
on DLC levels in human foods indicates that the greatest contribution to exposure
from the food supply is from animal fats in meat, dairy products, and fish.
REFERENCES
AEA Technology. 1999. Compilation of EU Dioxin Exposure and Health Data. Prepared for the
European Commission DO Environment. Oxfordshire, England: AEA Technology.
ATSDR (Agency for Toxic Substances and Disease Registry). 1994. Toxicological Profile for Chlo-
rinated Dibenzofurans (CDFs). Atlanta, GA: ATSDR.
ATSDR. 1998. Toxicological Profile for Chlorinated Dibenzo-p-dioxins. Atlanta, GA: ATSDR.
ATSDR. 2000. Toxicological Profile for Polychlorinated Biphenyls (PCBs). Atlanta, GA: ATSDR.
Axelson O. Sundell L. 1974. Herbicide exposure, mortality and tumor incidence. An epidemiological
investigation on Swedish railroad workers. Scand J Work Environ Health 11:21-28.
Bertazzi PA, Zocchetti C, Guercilena S. Consonni D, Tironi A, Landi MT, Pesatori AC. 1997.
Dioxin exposure and cancer risk: A 15-year mortality study after the "Seveso accident." Epide-
miology 8:646-652.
Bertazzi PA, Bernucci I, Brambilla G. Consonni D, Pesatori AC. 1998. The Seveso studies on early
and long-term effects of dioxin exposure: A review. Environ Health Perspect 106:625-633.
CDC (Centers for Disease Control and Prevention). 2001. National Report on Human Exposure to
Environmental Chemicals. Atlanta, GA: CDC.
A SUMMARY OF DIOXIN REPORTS, ASSESSMENTS, AND REGULATORYACTIVITY 51
Chen PH, Gaw JM, Wong CK, Chen CJ. 1980. Levels and gas chromatographic patterns of polychlo-
rinated biphenyls in the blood of patients after PCB poisoning in Taiwan. Bull Environ Contam
Toxicol 25:325-329.
EPA (U.S. Environmental Protection Agency). 2000. Exposure and Human Health Reassessment of
2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds. Draft Final Report.
Washington, DC: EPA.
FDA (U.S. Food and Drug Administration). 2000. Guidance for industry: Dioxin in anticaking agents
used in animal feed and feed ingredients; Availability. Fed Regist 65:20996-20997.
Fiedler H. Hutzinger O. Welsch-Pausch K, Schmiedinger A. 2000. Evaluation of the Occurrence of
PCDD/PCDF and POPs in Wastes and Their Potential to Enter the Foodchain. Prepared for
the European Commission DG Environment. Bayreuth, Germany: University of Bayreuth.
Hass RJ, Stevens FM. 2001. Dealing with dioxin: The state of analytical methods. Food Safety Mag
Dec 2000/Jan 2001.
Huisman M, Koopman-Esseboom C, Fidler V, Hadders-Algra M, van der Paauw CG, Tuinstra LGM,
Weiglas-Kuperus N. Sauer PJJ, Touwen BCL, Boersma ER. 1995. Perinatal exposure to poly-
chlorinated biphenyls and dioxins and its effect on neonatal neurological development. Early
Human Development 41:111-127.
IARC (International Agency for Research on Cancer). 1997. IARC Monographs on the Evaluation of
Carcinogenic Risks to Humans. Volume 69: Polychlorinated Dibenzo-para-Dioxins and Poly-
chlorinated Dibenzofurans. Lyon, France: World Health Organization.
IOM (Institute of Medicine). 1991. Nutrition During Lactation. Washington, DC: National Academy
Press.
Jacobson JL, Fein GG, Jacobson SW, Schwartz PM, Dowler JK. 1984. The transfer of polychlori-
nated biphenyls (PCBs) and polybrominated biphenyls (PBBs) across the human placenta and
into maternal milk. Am J Public Health 74:378-379.
Koopman-Esseboom C, Huisman M, Weislas-Kuperus N. Van der Paauw CG, Tuinstra LGM,
Boersma ER, Sauer PJJ. 1994a. PCB and dioxin levels in plasma and human milk of 418 Dutch
women and their infants. Predictive value of PCB congener levels in maternal plasma for fetal
and infant's exposure to PCBs and dioxins. Chemosphere 28:1721-1732.
Koopman-Esseboom C, Morse DC, Weisglas-Kuperus N. Lutkeschipholt IJ, Van der Paauw CG,
Tuinstra LG, Brouwer A, Sauer PJ. 1994b. Effects of dioxins and polychlorinated biphenyls on
thyroid hormone status of pregnant women and their infants. Pediatr Res 36:468-473.
Kuratsune M, Ikeda M, Nakamura Y. Hirohata T. 1988. A cohort study on mortality of Yusho
patients: A preliminary report. In: Miller RW, Wantanabe S. Fraumeni JF, eds. Unusual Occur-
rences as Clues to Cancer Etiology. Tokyo: Japan Scientific Societies Press. Pp. 61-68.
Landi MT, Bertazzi PA, Consonni D. 1996. TCDD blood levels, population characteristics, and
individual accident experience. Organohalogen Compd 30:290-293.
Landi MT, Consonni D, Patterson DG Jr, Needham LL, Lucier G. Brambilla P. Cazzaniga MA,
Mocarelli P. Pesatori AC, Bertazzi PA, Caporaso NE. 1998. 2,3,7,8-Tetrachlorodibenzo-p-
dioxin plasma levels in Seveso 20 years after the accident. Environ Health Perspect 106:273-
277.
Lanting CI, Fidler V, Huisman M, Boersma ER. 1998. Determinants of polychlorinated biphenyl
levels in plasma from 42-month-old children. Arch Environ Contam Toxicol 35:135-139.
Mocarelli P. Nee&am LL, Marocchi A, Patterson DG Jr, Brambilla P. Gerthoux PM, Meazza L,
Carreri V. 1991. Serum concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin and test results
from selected residents of Seveso, Italy. J Toxicol Environ Health 32:357-366.
NCEH (National Center for Environmental Health). 2003. Second National Report on Human Expo-
sure to Environmental Chemicals. NCEH Pub. No. 02-0716. Atlanta, GA: CDC.
Patandin S. Koopman-Esseboom C, de Ridder MA, Weisglas-Kuperus N. Sauer PJ. 1998. Effects of
environmental exposure to polychlorinated biphenyls and dioxins on birth size and growth in
Dutch children. Pediatr Res 44:538-545.
52
DIOXINS AND DIOXIN-LIKE COMPOUNDS IN THE FOOD SUPPLY
Patandin S. Dagnelie PC, Mulder PG, Op de Coul E, van der Veen JE, Weisglas-Kuperus N. Sauer
PJ. 1999. Dietary exposure to polychlorinated biphenyls and dioxins from infancy until adult-
hood: A comparison between breast-feeding, toddler, and long-term exposure. Environ Health
Perspect 107:45-51.
Riihimaki V, Asp S. Herberg S. 1982. Mortality of 2,4-dichlorophenoxyacetic acid and 2,4,5-
trichlorophenoxyacetic acid herbicide applicators in Finland: First report of an ongoing pro-
spective study. Scand J Work Environ Health 8:37-42.
Riihimaki V, Asp S. Pukkala E, Hernberg S. 1983. Mortality and cancer incidence among chlori-
nated phenoxyacid applicators in Finland. Chemosphere 12:779-784.
Scientific Committee on Food. 2000. Opinion of the Scientific Committee on Food on the Risk
Assessment of Dioxins and Dioxin-like PCBs in Food. European Commission, Health and
Consumer Protection Directorate-General. SCF/CS/CNTM/DIOXIN/8 Final. Brussels: Euro-
pean Commission.
Scientific Committee on Food. 2001. Opinion of the Scientific Committee on Food on the Risk
Assessment of Dioxins and Dioxin-like PCBs in Food. Update. European Commission, Health
and Consumer Protection Directorate-General. CS/CNTM/DIOXIN/20 Final. Brussels: Euro-
pean Commission.
Tran N. Wells C, Daniels C. 2002. A White Paper on Existing Dioxin Regulations and Monitoring
Program. Prepared for the Committee on the Implications of Dioxin in the Food Supply.
Washington DC: Novigen Sciences.
Vreugdenhil HI, Slijper FM, Mulder PG, Weisglas-Kuperus N. 2002. Effects of perinatal exposure
to PCBs and dioxins on play behavior in Dutch children at school age. Environ Health Perspect
110:A593-A598.
Weisglas-Kuperus N. Patandin S. Berbers GA, Sas TC, Mulder PG, Sauer PJ, Hooijkaas H. 2000.
Immunologic effects of background exposure to polychlorinated biphenyls and dioxins in Dutch
preschool children. Environ Health Perspect 108:1203-1207.
Winters DL, Anderson S. Lorber M, Ferrario J. Byrne C. 1998. Trends in dioxin and PCB concentra-
tions in meat samples from several decades of the 20th century. Organohalogen Compd 38:75-
78.
Wolfe WH, Michalek JE, Miner JC, Rahe A, Silva J. Thomas WF, Grubbs WD, Lustik MB, Karrison
TG, Roegner RH, Williams DE. 1990. Health status of Air Force veterans occupationally
exposed to herbicides in Vietnam. I. Physical health. JAm Med Assoc 264:1824-1831.
