Volume 1, Number 3
A Gossman Consulting, Inc. Publication
March 1995


Jim Woodford and David Gossman

General Comments:

A basic tenet of the EPA dioxin reassessment boils down to the implied assumption that if dioxin can cause cancer at a given dose, then no dose is safe. Philip H. Abelson, Editor of Science Magazine, in a September 9, 1994 Science magazine editorial, identified several flaws in this line of thinking. One in particular has been demonstrated by Bruce Ames, originator of the widely used Ames carcinogen test. Abelson writes, "Ames and others have pointed out that huge doses of nongenotoxic substances are accompanied by toxicity, cell death, and cell replacements. This creates conditions favorable for growth of tumors. At doses in which cellular death does not occur, tumors would not be produced by nongenotoxic substances."

Abelson goes on to point out, in his September 9, 1994 Science magazine editorial, that there is data cited in this EPA dioxin reassessment where low doses of dioxin administered to female rats resulted in tumor incidence that was lower than the control group; when high doses were given, the incidence of certain tumors was greater than in controls, while for other tumors the incidence was lower. These examples were used by Abelson to question government agency assumptions that carcinogenic effects observed at high exposures are predictive of effects at minuscule exposures.

In a November 18, 1994 Science magazine letter-to-the-editor, A.M. Monro of Pfizer Central Research in Groton, CT discussed data that indicates that these mixed responses are widespread. Monro and a fellow researcher analyzed the results of 124 "experiments carried out by the U.S. National Toxicology Program on 37 chemicals and found that tumor increases were observed in 41% of the experiments relative to controls and decreases were observed in 46%; in 22 experiments, simultaneous increases and decreases were observed."

Monro also points out that "Mutagenicity is widely regarded as a property that predisposes a chemical to display transspecies carcinogenic activity, often with multiple target organs. Monro notes that in his study, "five chemicals associated with multiple organ carcinogenicity were, as expected, all positive in the bacterial mutation (Ames) test; however, nine Ames-positive chemicals produced increases and decreases in tumor incidence, and three such chemicals produced only decreases in tumor incidence." In the EPA dioxin reassessment, EPA has used data (the data that demonstrates an increase in tumors) rather than looking at/including all of the data (which also demonstrates decreases in tumors). In so doing, EPA gives the impression of using data to support a predetermined conclusion. Monro's last paragraph takes this predetermined agenda one step further and is cited as follows:"A fundamental tenet of governmental risk assessment is that a chemically induced increase in tumor increase in animals implies a carcinogenic risk to humans exposed to the chemical." But here is where Monro invokes the logical corollary and departs from EPA data manipulation, "Logically, it should follow that a chemically induced decrease in tumor incidence implies an anticancer effect in exposed humans. To decide which of these effects is more relevant to the overall well being and survival of an individual may require further investigation of mechanisms, but to base a regulatory decision on analysis of only part of the data (tumor increases) is scientifically unsound."

Robert P. Zendzian, a Senior Pharmacologist for EPA, joins the assault on the no threshold model used by EPA. The apparent originators/ perpetrators of this concept presented this model originally, "not because it appears to fit the facts, but rather because it was the most conservative way of treating the data. In order to advance the conservative approach, they did not extrapolate from an effect dose to zero dose, but presented the upper 99% confidence limit of that extrapolation." If there is one thing of which we can be certain, it is that if one is not exposed to a foreign chemical then one can certainly not get cancer from the foreign chemical. As Zendzian points out, "at zero exposure it cannot produce cancer." This bears restatement but with revealing qualification, which Zendzian provides; "At zero dose, the cancer expectation should be zero (± zero). The extrapolation used, in fact, all extrapolations (including our own upper 95% confidence limit), gives a positive cancer producing potential at zero dose." EPA intent/ assumptions are so conservative that we start off with the assumption that there is a cancer causing effect of any given substance even if there is no exposure. What else can this indicate but that there is a predetermined agenda concerning any substance investigated by the EPA, in this case dioxins?

R.C. von Borstel, of the Department of Biological Sciences from the University of Alberta Canada, cites a National Institute of Environmental Health Sciences study which takes a fresh look at animal test data of carcinogens and their analogs. The study was designed to test the effects of known human carcinogens on mice, the control being analogs of these carcinogens that were not human carcinogens. Borstel points out that a reexamination of the original data unexpectedly revealed "that most of the chemicals tested for carcinogenicity exhibited anticarcinogenic responses, actually reducing the spontaneous cancer incidence from that found in the untreated controls." EPA's own dioxin reassessment recognizes that "Under some circumstances, exposure to TCDD elicits beneficial effects. ...TCDD-induced changes in estrogen metabolism may alter the growth of hormone-dependent tumor cells, producing a potential anticarcinogenic effect...These (and perhaps other) potentially beneficial effects of TCDD further complicate the risk assessment process for dioxin . [Volume I: Health Assessment Document for 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds (EPA/600/BP-92/001a) - Page 2.23, Section 2.8 - Mechanistic Information and Risk Assessment] Research performed by Stephen Safe et. al., cited in Volume I of the Health Assessment Document, which addresses the antiestrogen effect of TCDD, is mentioned so briefly that it is easily passed over (cited on page 3-26, listed as a reference on page 3-48). Recently published research (Dec. 7, Journal of the National Cancer Institute) by Hong Lui further supports the antiestrogenic effects of both dietary and environmental antiestrogens, which would include TCDD.

EPA is to be commended on the volumes of data that are reviewed in this dioxin reassessment. The data is also presented in a fairly balanced manner and is quite informative. The problem comes with the summary statements which, unfortunately, reflect only one side of the discussion and assign blame based upon data that is preliminary/inadequate, by EPA's own admission.

Volume I: Health Assessment Document for 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds (EPA/600/BP-92/001a)

Page 1-5, section

This text addresses Gastrointestinal Absorption in Humans. At the bottom of this page EPA refers to a" limited database" but then goes on to state that the limited database "suggests that there are no major interspecies differences in the gastrointestinal absorption of these compounds." A cursory review of Appendix C, on bioavailability, in Volume II Properties, Sources, Occurrence and Background Exposures (EPA/600/6-88/005Cb) reveals that there is quite a difference in gastrointestinal absorption depending upon how the compounds are introduced into the system. Interspecies comparisons just compound the problems of gastrointestinal absorption. Parts of this is addressed to some extent in section on pages 1-6 & 1-7.

Research that included dioxin contaminated flyash treatment in rats is briefly discussed on page 1-6. Rats were fed the same levels of dioxin contamination using different methods. One group was fed actual contaminated flyash and another group was fed an extract from the contaminated flyash. Direct feeding of the contaminated flyash resulted in considerably lower hepatic contamination levels than feeding the rats extract from the contaminated flyash, suggesting that consumption of flyash-like materials is of lesser concern than other exposure vehicles.

Page 2.23, Section 2.8 - Mechanistic Information and Risk Assessment

One paragraph in this "summary" section is very much worth noting. Under some circumstances, exposure to TCDD elicits beneficial effects. For example, TCDD protects against the carcinogenic effects of polycyclic aromatic hydrocarbons in mouse skin; this may reflect the induction of detoxifying enzymes.... In other situations, TCDD-induced changes in estrogen metabolism may alter the growth of hormone-dependent tumor cells, producing a potential anticarcinogenic effect.... These (and perhaps other) potentially beneficial effects of TCDD further complicate the risk assessment process for dioxin . There have been absolutely no mention of the "potentially beneficial effects of TCDD" in any EPA press releases. The controversy over beef consumption apparently prompted some EPA spokesperson to point out that the benefits of eating far outweigh the risk of consuming the minute amounts of dioxins in food that is eaten. In this section of the dioxin reassessment we also learn that there may actually be beneficial effects of TCDD exposure. Too bad that EPA did not provide a balanced press release with the release of the dioxin reassessment.

Page 3-34, Section 3.7 - Conclusions

EPA points out that "When comparing species and strains, it is clearly evident that there are enormous differences in the sensitivity to specific TCDD-induced toxicities. This conclusion is valid for almost all the responses studied." These recognized "enormous differences" would seem to further augment the argument that a human is not a guinea pig and therefore likely will not respond the same. In fact, human subjects are discussed in section 4.12, on page 4-35. The study cited reported findings from immunological assessment of 41 persons with documented adipose tissue levels of TCDD resulting from occupational, recreational, or residential exposure. The highest TCDD level found was 750 ppt. No adverse clinical disease was associated with TCDD levels in these subjects. (emphasis added) Also, a study conducted on a group of children, six years after the Seveso, Italy explosion, found no specific health problems correlated with dioxin exposure in the children.

It is of interest to note that little use/mention was made of one of the most widely publicized dioxin exposure events in history, the Seveso Italy incident. Only two references were found in the Chapter 5 bibliography (a chapter that addressed human effects more extensively than others) listed on pages 5-74 thru 5-93. There was only one readily discernible reference in Chapters 1 & 4. All references revealed no long-term negative effects of the dioxin exposure at Seveso, Italy. The following Seveso, Italy references were identified in this volume:

pg. 1-22 (dealt with factors other than dioxin exposure)

pg. 4-34 "no specific health problems were correlated with dioxin exposure in these children"

pg. 5-19

pg. 5-23 "Studies in humans have not clearly identified an association between TCDD exposure and structural malformations."

pg. 5-34

Volume II: (EPA/600/BP-92/001lb)

The most widely known and probably the most widely studied incident of dioxin exposure is the Seveso, Italy incident. For the most part, the long term studies are not revealing the doom and gloom health effects that EPA would have people believe will be caused by dioxin exposure.

Page 7-8, section 7.5

Chloracne is a documentable effect of high dioxin exposure. However, "Many highly exposed persons do not develop it." In addition, "Exposure to other dioxin-like chemicals that can be found in the workplace may produce a form of chloracne that could be indistinguishable from that produced by dioxin." So, even the one recognized effect of over-exposure to dioxin is not totally definitive.

Page 7-35, section 7.5.5 - Summary

A Seveso, Italy study is cited in the final paragraph of this section that points out "a deficit of breast cancer and endometrial cancer" in women living in dioxin contaminated areas. Another study, cited in this same paragraph, found similar results concerning breast cancer. Again, here are potentially positive effects from dioxin/TCDD exposure that received no attention upon release of this dioxin reassessment and has not been brought to the public's attention by EPA spokespersons.

Page 7-66, section 7.8.2

The Seveso, Italy incident does get five pages of discussion in section 7.8.2, beginning on page 7-66. Ten year Seveso, Italy studies are cited where "No excesses of mortality from lung cancer, stomach cancer, or all cancers combined are apparent." (page 7-67) Seveso, Italy studies, of limited significance, are also discussed in reference to non-cancer effects in section on pages 7-96 and 7-97. The Seveso, Italy incident is discussed again on pages 7-202 and 7-203, whereby "the rate of birth defects occurring early in the observation period (first quarter of 1977) did not differ from the rate of birth defects occurring later in the observation period...and there were no discernible patterns of defects within or between the exposure groups." Seveso, Italy is again discussed in the Summary beginning on page 7-238 (in particular on page 7-241) in what appears to be an attempt to cast doubt on those studies.

Page 7-73, section 7.9 Conclusions

One study, results of which have stood up to extensive criticism and a great deal of subsequent research, found a reduced estimated risk in later studies. The final concluding paragraph for this section of the report [ Chapter 7. Epidemiology/Human Data; Part A: Cancer Effects] contains a sentence which states: " although there are uncertainties associated with the epidemiologic evidence that could have influenced risk estimates, the overall weight of evidence from the epidemiologic studies suggests that the generally increased risk of cancer is more than likely due to exposure to TCDD. (emphasis added) Suggesting a relationship? Perhaps. Authoritatively conclusive? Not by scientific standards.

Page 7-243, section 7.15.1 - Effects Having a Positive Relationship with Exposure to 2,3,7,8-TCDD

Even in this section, where EPA tries to highlight the effects which can be "positively" associated with TCDD exposure, there are also studies which are counter-indicative of these same effects. In short, some studies seem to show there is an effect, some studies seem to show that there is not. EPA seems to have taken the approach that they will ignore the studies that do not show an effect and concentrate on the studies that do. This is an obvious bias generally unacceptable in a purely scientific document.

General comment

In general, EPA is to be commended for what appears to be exhaustive research on the studies of dioxin related effects on the human population. EPA is also to be commended on the reasonably balanced presentation of this research. It is unfortunate however, with this dioxin reassessment, that EPA continues a trend evident in two previous documents, The CKD Report to Congress & The Combustion Emission Technical Resource Document (CETRED). That trend is to ignore what the data says, or manipulate the data in such a fashion that it indicates a predetermined conclusion.

Cursory review of the comments in section 7.13, Review of Effects Associated With Exposure to 2,3,7,8-TCDD, found on pages 7-106, 7-118, 7-121, 7-129, 7-134, 7-139, 7-158, 7-178, 7-185 and 7-188 do not seem entirely consistent with the resulting human model recommendations found in sections 8.4 and 8.5, beginning on page 8-73. EPA discusses differences and inconsistencies in these sections, but then seems to ignore them in their human model recommendations, going on to reach some predetermined conclusion.

Volume III: (EPA/600/BP-92/001c)

Page 9-1

It is on the first page of this document that EPA makes statements/accusations that are more innuendo than factual, yet the statement is made in such a fashion as to imply great danger from dioxin exposure; "...human studies demonstrate that exposure to dioxin and related compounds is associated with subtle biochemical and biological changes whose clinical significance is as yet unknown.... Laboratory studies suggest the probability that exposure to dioxin-like compounds may be associated with other serious health effects including cancer. Human data, while often limited in their ability to answer questions of hazard and risk, are generally consistent with the observations in animals." EPA provides no specific citations for the "subtle biochemical and biological changes" charge made in this passage. The fact that they do not use specific citations implies that they have no case to summarize. Instead, EPA resorts to Greenpeace type rhetoric which fans "fear-of-the-unknown" flames. EPA even qualifies their claims by stating that human data is "often limited in their ability to answer question of hazard and risk" but that didn't stop them from making deleterious claims.

Page 9-9

Examples of combustion and incineration sources are given here, yet there is no mention of cement kilns.

Page 9-11

EPA qualifies the questionable significance of their data for cement kilns with such phrases as "estimates were derived from data from emission tests at relatively few facilities" and "limited number of measurements", yet this does not prevent EPA from alleging that cement kilns are major contributors to dioxin emissions. EPA has taken preliminary data, which they point out as having a high degree of uncertainty, and pointed an accusatory finger at cement kilns.

Page 9-14

In the last paragraph of section 9.4.1, EPA discusses atmospheric deposition and admits that "it is unclear whether atmospheric deposition represents primarily "new" contributions of dioxin and related compounds from all media reaching the atmosphere or whether it is "old" dioxin and related compounds that persist and recycle in the environment." An accurate atmospheric deposition determination concerning "old vs. new" is a major issue. Not only does EPA accuse cement kilns of being major contributors based upon preliminary emission data, biased due to BIF compliance requirements, but they do so while admittedly not knowing the role of atmospheric deposition.

Page 9-15

Even the most controversial suggestion from this dioxin reassessment, that food is the predominant pathway of exposure (particularly beef), is highly qualified by the EPA when they state that this "remains to be validated in the United States." Frankly, to create the type of uproar and alarm that was created by the initial publication of this conclusion based upon a "limited number of samples" borders on irresponsible.

Page 9-25

In terms of transpulmonary absorption, EPA makes an incriminatory statement, again based on "limited data" and also points out that "no data from humans or primates are available." This did not stop EPA from making the incriminatory statement. Why let science get in the way?

"The use of incineration as a means of solid and hazardous waste management results in the emission of vapors and contaminated particles that may contain TCDD and related compounds into the environment. Thus, exposure to TCDD and related compounds may result from inhalation of contaminated fly ash, dust, and soil or from ingestion of air-transported particles are deposited on fruits and vegetables. Direct exposure by the inhalation route is usually relatively low as a percentage of overall intake. Systemic effects occur in animals after pulmonary exposure to TCDD, suggesting the transpulmonary absorption of 2,3,7,8-TCDD and 2,3,7,8-TCDD was similar to that observed following oral exposure. These limited data provide evidence of efficient transpulmonary absorption after intratracheal instillation in laboratory animals. No data from humans or primates are available to address this issue." (emphasis added) However, these data supposedly provide support for the inference that efficient absorption will occur when vapors and particulates containing dioxin and related compounds are inhaled by humans.

In addition, EPA previously pointed out in their discussions about photodegradation (Volume II: Properties, Sources, Occurrence and Background Exposures (EPA/600/6-88/005Cb, pg 2-35) that "no significant degradation was observed in 11 photodegradation experiments" of dioxins adsorbed to five different fly ashes. If the dioxins are so tightly bound by the fly ash, as indicated by this previous discussion, what is the likelihood that "inhalation of contaminated fly ash" would be a factor even if there was proof of transpulmonary absorption in humans?

Page 9-36

EPA makes a statement here that casts serious doubt about their intentions. "Qualitatively speaking, however, almost every response can be produced in every species if the appropriate dose is administered." How ridiculous! The same thing can be said about water. Drowning can be induced in all species as well "if the appropriate dose is administered" but at many levels of use/exposure, water is harmless. It is also beneficial, just as some dioxin studies indicate.

Section 9-11

First Bold Conclusion - page 9-74

EPA does not even mention the potentially positive effects of dioxin exposure. The potentially positive effects are equally as valid as what EPA calls "a broad spectrum of biochemical and biological effects."

Conclusion on page 9-75

EPA concludes that "the major route of human exposure is through ingestion of food", although just a few pages earlier EPA qualified this conclusion by stating that "This conclusion, that food is the predominant pathway of exposure, remains to be validated in the United States." (page 9-15)

Conclusion on page 9-78

EPA points out that "effects elicited by exposure to 2,3,7,8-TCDD are shared by other chemicals that have a similar structure and Ah receptor-binding characteristics." This could more accurately be restated to reflect the fact that very little of the voluminous studies cited in this dioxin reassessment definitively indict TCDD. Much of the human data came from high exposure situations with confounding chemical factors.

Conclusion on page 9-79

EPA makes claims in this conclusion that lead a reader to see adverse effects from dioxin exposure. As a matter of fact, adverse/toxic effects is used in this section no less than nine times in five short paragraphs. Nowhere in this concluding section are the potentially positive effects of dioxin exposure elicited. A more telling summary statement is found on page 9-80: "The mechanistic relationships of biochemical and cellular changes seen at very low levels of exposure to production of adverse effects detectable at higher levels remain uncertain and controversial. (emphasis added).

Conclusion on page 9-81

At least EPA borders on objectivity in this conclusion by stating, "It is not currently possible to state exactly how or at what levels humans in the population will respond." Unfortunately, EPA then goes on to state that "the margin of exposure between background levels and levels where effects are detectable in humans in terms of TEQs is considerably smaller than previously estimated."

This entire conclusion relies on hedge words to stretch inconclusive data into making EPA's point that dioxins cause problems at lower levels than previously thought. The only statement in the entire seven paragraph conclusion that is stated in a factual manner is that "Average human daily intakes of TCDD are in the range of 0.3-0.6 pg TCDD /kg body weight/day." But, to state this as fact really stretches the "factual" aspects of the "limited/ confounded/uncertain" data that was used to make this statement. One of the more accusatory hedge statements is found at the end of this section. After pointing out that "Few changes in the immune system in humans associated with dioxin body burdens have been detected when exposed adult males have been studied" EPA states that "Despite the possibility that these compounds may be immunotoxic at some level in humans [one must assume that the word "possibility " is used here in the highly conjecturitive theoretical sense] the impact of dioxin and related compounds on the immune system and implications for characterizing risk are largely unknown at this time." Even when a possible effect is "largely unknown at this time" EPA apparently feels compelled to try to make an accusation.

Final Conclusion Statement, page 9-87

This final statement has been misinterpreted with particularly over reaching effects since it was repeatedly misquoted in the media immediately following the release of this report. The conclusion is quoted as follows:

"Based on all of the data reviewed in this reassessment and scientific inference, a picture emerges of TCDD and related compounds as potential toxicants in animals with the potential to produce a spectrum of effects. Some of these effects may be occurring in humans at very low levels and some may be resulting in adverse impacts on human health."

The interpretation of this statement was more like this; Based on all of the data reviewed in this reassessment, TCDD and related compounds have been found to be toxicants in animals and produce a spectrum of effects. Some of these effects also occur in humans at very low levels resulting in adverse impacts on human health. It is difficult to believe that this statement was not carefully constructed so as to convey the preceding interpretation.

Contrast this statement with one from The French Academy of Sciences and its Committee of Applied Sciences (CADAS), which has just published a dioxin report with diametrical conclusions to this EPA dioxin report. In only 80 pages (vs. 2,000 for the EPA), CADAS reports that "Contrary to popular opinion, there is no evidence to suggest that dioxins and their related compounds constitute a major risk to public health." According to the director of CADAS, the two reports are very much in agreement until it comes to the conclusion. The report states that "PCDD/F...toxicity in man is infrequent and not serious." It goes on to say that "no fatal case of poisoning by these products has ever been reported." CADAS also states that the World Health Organization (WHO) daily acceptable dose of ten picograms/ kg/day "seems today a prudent and realistic guide to be retained and used for the management for the risk of dioxins to public health."

EPA did in fact make a similar statement in their final concluding paragraph. Unfortunately, it was not part of the bold printed final concluding statement. EPA very clearly states that " there is currently no clear indication of increased disease in the general population attributable to dioxin-like compounds." That pretty much sums up the essence of the whole dioxin reassessment even though EPA apparently chooses to have the general population believe otherwise.