Dioxin and cancer: a critical review

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Abstract

2,3,7,8-tetrachlordibenzo-p-doxin (TCDD) would not have been designated as a Group 1 carcinogen by IARC had there not been a change in the criteria used for inclusion in this category. Furthermore, there is no precedent for indicating, as did IARC, that a single chemical acts as a pluripotential carcinogen by modestly increasing human risk for all cancer while not increasing the risk for any single cancer at least moderately. IARC moved TCDD to Group 1 based on mechanistic considerations focusing on the Ah receptor. However, while occupancy of the Ah receptor by TCDD may be necessary for its toxicity, it is not sufficient for toxicity or for potential carcinogenicity. Animal evidence relating TCDD exposure to cancer is much stronger than that for humans. However, the large inter-species variation in the relevant dose–response slopes severely limits generalizations from animals to humans. The epidemiologic studies of occupational exposures, pesticide applicators, and community exposures following industrial accidents, notably Seveso, have generated overall relative risks of all cancer of about 1.0. Only case-control studies of soft-tissue sarcoma and non-Hodgkin’s lymphoma, all by the same investigator, reported elevated risk from TCDD exposure. However, these results have not been replicated. The representation that a chemical compound (TCDD) would be a late-stage carcinogen for all types of cancer has no precedent and lacks biological foundation. Virtually all late-stage or promoting carcinogens (e.g., hepatitis-C virus, asbestos, and estrogens) cause a very limited number of forms of cancer. The exposure–response meta-analysis of TCDD and cancer developed by the United States Environmental Protection Agency (USEPA) is seriously compromised by its failure to adequately fit the data. The studies used by the USEPA also likely underestimate TCDD body burdens and may be confounded by smoking and other occupational exposures. Furthermore, the use of a linear dose–response model by the USEPA is scientifically unjustified since the underlying model of TCDD as a human carcinogen is based primarily on its supposed receptor-mediated, non-genotoxic (or promotional) mode of action. There are few examples of an agent being suspected as a human carcinogen for decades and then eventually moving into the category of “known” human carcinogens. In contrast, there are hundreds of compounds that remain for decades on lists of “suspected” human carcinogens despite the lack of confirming evidence. The long-term accumulation of negative, weak, and inconsistent findings suggests that TCDD eventually will be recognized as not carcinogenic for humans.

Introduction

This document is a three-part review of the evidence on the hypothetical cause–effect relationship between exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (hereafter, TCDD) and cancer in human beings. Part I focuses on the evidence available through 1997 with emphasis on the review done by the International Agency for Research on Cancer (IARC) in its 1997 Monograph 69 (IARC, 1997). IARC’s decision to place TCDD in Group 1 (agents with sufficient evidence of carcinogenicity for humans) is unsupportable because it depends on an analogy of mechanisms of carcinogenicity between animals and humans and on an inappropriate evaluation of the epidemiologic evidence.

Part II presents a similar approach to subsequent epidemiologic reports and concludes that the most recent literature further weakens the evidence concerning the potential carcinogenicity of TCDD in humans. Part III addresses the current version of the US Environmental Protection Agency’s ongoing risk assessment.

Because of the many negative studies of TCDD and cancer in humans and the weaknesses and inconsistencies even among the positive studies published before and since 1997, we suggest that the existing evidence would exclude TCDD from IARC’S Group 1.

Section snippets

Part I. The IARC evaluation

The carcinogenicity of TCDD for humans has been controversial for a long time, but it was its designation in 1997 as carcinogenic to humans (Group 1) by the IARC of the World Health Organization that focused the controversy on the specific issues of the epidemiologic evidence linking TCDD with cancer and on TCDD’s possible mode of action as a carcinogen (IARC, 1997). For decades, the necessary criterion for inclusion of an agent in Group 1 was that there existed sufficient evidence of

Part II. Epidemiologic studies after 1997

In this section we review epidemiologic studies appearing after the publication of the IARC Monograph 69. Special attention is given to studies that were published in major journals or that received wide publicity.

In the update of the NIOSH follow-up study, Steenland et al. (1999) state that, “In 1997, the International Agency for Research on Cancer (IARC) classified 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a group 1 human carcinogen, based largely on four highly exposed industrial cohorts

Part III. Comments on USEPA’s dose–response assessment and risk characterization of the potential human carcinogenicity of TCDD

As concluded previously, the data available to IARC for its 1997 monograph, and all data published subsequent to that review do not support a conclusion that TCDD is carcinogenic in humans. It is inappropriate, therefore, to engage in detailed evaluations of a potential dose–response relationship between TCDD and a cancer endpoint. Nevertheless, USEPA conducted such an evaluation in the Integrated Summary and Risk Characterization Section of its reassessment (US EPA, 2000). For this reason, it

Conclusion

It is clear from this review that the evidence does not support the IARC’s classification of TCDD as a Group 1 carcinogen. In fact, the evidence indicates that TCDD is not carcinogenic to human beings at low levels and that it may not be carcinogenic to them even at high levels.

Acknowledgements

The assistance of Pam Chapman and Sean Hays is gratefully acknowledged. The project was sponsored by the Chlorine Chemistry Council.

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