Dioxin and cancer: a critical review

Our plain-English summary of Dioxin and cancer: a critical review, by P. Cole, D. Trichopoulos, H. Pastides, et al (Regulatory Toxicology and Pharmacology, 2003).

The study

• Authors: P. Cole, D. Trichopoulos, H. Pastides, T. Starr, J.S. Mandel
• Journal: Regulatory Toxicology and Pharmacology
• Published: 2003;38(3):378-88
• Type of article: Review
• Cited by: 117 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This was a critical review, not a new study, of evidence on whether TCDD (dioxin) causes cancer in humans. The authors examined the 1997 International Agency for Research on Cancer (IARC) evaluation, later studies, and a US Environmental Protection Agency (USEPA) risk assessment. They argued TCDD could not have been classed as Group 1 under IARC's earlier criteria. Citing a worker study by Kogevinas and colleagues, they reported an all-cancer standardized mortality ratio (SMR) of 1.1 (95% confidence interval 1.0 to 1.2). Comparing two reports on one US worker cohort, they calculated a non-significant all-cancer SMR of 108 (100 meaning deaths as expected) for six added years of follow-up, with no soft-tissue cancer deaths then. Asbestos, not the article's subject, came up in three ways. Two mesothelioma deaths among these workers could reflect asbestos exposure, the authors said. They called asbestos a carcinogen selective in its effects. They faulted the USEPA for not adequately adjusting for possible confounding by asbestos and other exposures. The authors concluded TCDD is not carcinogenic to humans at low levels and may not be even at high levels.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: critical review of published evidence (three parts: the IARC 1997 evaluation, epidemiologic studies after 1997, and the USEPA dose-response assessment); no new data collected
• Who was studied: Published evidence on TCDD and cancer: the IARC Monograph 69 (1997) evaluation and the studies in it (industrial worker cohorts, the Seveso accident population, herbicide applicators, Vietnam veterans, case-control studies), studies published after 1997, and the USEPA reassessment
• Exposure: TCDD (dioxin) and phenoxy herbicides and chlorophenols, from chemical production, industrial accidents and herbicide use. Asbestos was not the exposure studied; it was discussed as a possible confounder in worker studies and the USEPA assessment, and as an example of a selective carcinogen.
• Main results:
  • The authors stated that TCDD could not be classed as a Group 1 (known human) carcinogen under IARC's criteria in use before 1990.
  • As reported by the authors, the Kogevinas et al. (1997) international cohort of exposed workers had an all-cancer SMR of 1.1 (95% confidence interval 1.0 to 1.2).
  • Comparing the 1991 and 1999 reports on the NIOSH worker cohort, the authors calculated that the six added years of follow-up contained 112 all-cancer deaths, with a non-significant SMR of 108. This SMR is on a scale where 100 means deaths as expected (103.7 deaths were expected).
  • In the same comparison, no connective-tissue or soft-tissue cancer deaths occurred in the NIOSH cohort during the six added years.
  • As reported by the authors, the update of the Seveso accident population through 1996 (Bertazzi et al., 2001) gave rate ratios for all cancer mortality of 1.0 in the two high-exposure zones.
  • Discussing the NIOSH worker cohort, the authors said that two deaths from mesothelioma could reflect workplace asbestos exposure. The type of mesothelioma was not stated.
  • The authors described asbestos, with ethanol, hepatitis-C virus and steroid hormones, as a non-genotoxic carcinogen that is selective in its effects.
  • The authors criticized the USEPA analysis for not adequately adjusting for possible confounding exposures, including asbestos.
  • Citing Starr (2001), the authors reported that the USEPA meta-analysis data were fit adequately by a model with no TCDD effect when unexposed workers' cancer mortality was allowed to differ from the reference populations.
• The authors' conclusion: The authors concluded that the evidence does not support IARC's Group 1 classification of TCDD, that TCDD is not carcinogenic to humans at low levels, and that it may not be carcinogenic even at high levels.

Topics

Medical terms in this study, explained in our Lexicon: IARC, Dose-response relationship, Occupational Exposure, Relative Risk, Sarcoma, Meta-Analysis, Carcinogenic.

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