Carcinogenicity of EBDCs. (Perspectives Correspondence).

In 1997 we published an article in EHP on cytogenetic and thyroid hormonal changes in 49 heavily exposed workers applying ethylene bisdithiocarbamate (EBDC) fungicide to tomatoes, based on a collaborative study done by the U.S. National Institute for Occupational Safety and Health and the Institute of Public Health in Mexico (Steenland et al. 1997). EBDCs are a common class of fungicides (e.g., mancozeb, maneb) that are metabolized to ethylene thiourea (ETU) in workers after primarily dermal absorption. In experiments in rats, ETU caused decreased thyroid hormone [thyroxine ([T.sub.4])], increased thyroid-stimulating hormone (TSH), and thyroid tumors. We sought to determine whether workers exposed to ETU showed thyroid hormone changes compared to a nonexposed comparison group (n = 31). We also looked at sister chromatid exchange (SCE) and chromosomal translocations (balanced chromosomal aberrations that are not cell lethal) in the lymphocytes of exposed workers and nonexposed controls.

In this study (Steenland et al. 1997), we found a mean urinary ETU level in the exposed applicators of 58 ppb, although 34% had levels below the limit of detection (most ETU is excreted within 24 hr). All 31 nonexposed controls had levels below the limit of detection. We found a significant increase in TSH (p = 0.05) in applicators versus nonexposed controls, suggesting that increased TSH compensated for a thyroid hormone decrease (altered homeostasis). We also found increased SCEs (p = 0.03) and chromosomal translocations (p = 0.05) in the applicators versus the nonexposed population, suggesting cytogenetic damage due to ETU.

Subsequently, in 2001 the International Agency for Research on Cancer (IARC) downgraded ETU from group 2B (possibly carcinogenic to humans) to group 3 (not classifiable as to carcinogenicity in humans) (IARC 2001). Although IARC recognized that ETU was carcinogenic in animals, it judged that the mechanism by which cancer occurred in animals was not relevant to humans. Specifically, IARC. (2001) stated that cancer occurred via a

   ... nongenotoxic mechanism, which involves
   interference with the functioning of thyroid peroxidase
   resulting in a reduction of circulating thyroid
   hormone concentrations and increased secretion of
   thyroid-stimulating hormone. Consequently, ETU
   would not be expected to produce thyroid cancer
   in humans exposed to concentrations that do not
   alter thyroid hormone homeostasis.

The use of mechanisms as a basis for classifying or reclassifying agents as carcinogens has been controversial, sometime leading to upward classifications (ethylene oxide and TCDD), but more often to downward ones (e.g., ETU, atrazine, phthalates, saccharin) (Tomatis 2002).

The IARC ETU working group (IARC 2001) cited our article (Steenland et al. 1997) as indicating cytogenetic damage in workers "presumably" exposed to ETU (apparently discounting the urinary evidence). With regard to our findings of increased TSH, indicative of altered thyroid hormone homeostasis in ETU-exposed workers, they noted that the workers had a "marginal increase in the serum concentration of TSH but no change in that of thyroxine ([T.sub.4])." As noted above, the "marginal" increase was statistically significant, albeit not clinically important (and normal [T.sub.4] due to increased TSH might be expected). The working group chose to ignore this evidence of altered homeostasis (IARC 2001).

It seems surprising that the IARC working group downgraded ETU based on a lack of evidence that ETU alters thyroid homeostasis in humans, while the only study that has looked at this question in humans did indeed find such evidence.

I would like to bring this apparent discrepancy to the attention of' the environmental health community and to sound a cautionary note regarding the possible human carcinogencity of EBDC fungicides, which are used extensively throughout the world. In the United States, the U.S. Environmental Protection Agency cancelled the use in 1992 of EBDC fungicides on 11 crops due to the evidence of animal carcinogenicity but continues to permit their use on a wide variety of nut, fruit, and vegetable crops.

The author declares he has no conflict of interest.

Kyle Steenland

Emory University School of Public Health

Atlanta, Georgia

E-mail: [e-mail]

REFERENCES

IARC. 2001. Ethylene thiourea. IARC Mongr Eval Carcinog Risks Hum 79:659-701.

Steenland K, Cedillo L, Tucker J, Hines C, Sorensen K, Deddens J, et al. 1997. Thyroid hormones and cytogenetic outcomes in backpack sprayers using EBDC fungicides in Mexico. Environ Health Perspect 105:1126-1130.

Tomatis L. 2002. The IARC Monographs program: changing attitudes towards public health. Int J Occup Environ Health 8:144-152.

Carcinogenicity of EBDCs: Response

The IARC (International Agency for Research on Cancer) Monographs on the Evaluation of Carcinogenic Risks to Humans deal with all kinds of agents and exposures in the human environment that may present a cancer hazard. As of October 2002 (Volume 84), the program has evaluated 888 agents and exposures, including ethylene thiourea (ETU) recently (IARC 2001) and some of the ethylene bisdithiocarbamate (EBDC) fungicides earlier. The monographs do not formally evaluate the carcinogenicity of metabolites or other endogenously formed substances, although evidence on the biological activity of metabolites may provide important supporting data for evaluating the carcinogenicity of parent substances. The monographs evaluated ETU as a primary environmental exposure (IARC 2001).

Monograph working groups, which are composed of independent scientific experts, must follow the criteria set forth in the "Preamble" to the monographs (IARC 1992) when making overall evaluations of carcinogenicity to humans. Those criteria are refined from time to time. In 1992 (when Lorenzo Tomatis was director of IARC) the definition of Group 3--not classifiable as to carcinogenicity to humans--was modified as follows (IARC 1992):

   This category is used most commonly for agents,
   mixtures and exposure circumstances for which
   the evidence of carcinogenicity is inadequate in
   humans and inadequate or limited in experimental
   animals. Exceptionally, agents (mixtures) for
   which the evidence of carcinogenicity is inadequate
   in humans but sufficient in experimental animals
   may be placed in this category when there is strong
   evidence that the mechanism of carcinogenicicy in
   experimental animals does not operate in humans.
   [italics added]. Agents, mixtures and exposure circumstances
   that do not fall into any other group
   are also placed in this category.

This definition has not changed since it was first established in 1992. It is the responsibility of individual working groups to decide when the italicized criterion applies.

The Monographs Programme has convened several scientific workshops to address certain modes of carcinogenic action in experimental animals and to develop criteria for assessing the roles of mechanistic evidence in establishing overall evaluations of carcinogenicity. The proceedings of these workshops have been published, and the consensus reports from these publications are made available as guidance to monograph working groups and are also freely available on the monographs website (IARC 2003). Mechanisms of action of agents that cause thyroid follicular cell tumors in experimental animals have been studied extensively and include both genotoxic and nongenotoxic processes; these mechanisms have been specifically addressed in several papers in Capen et al. (1999).

Thyroid follicular cell neoplasms are commonly seen in bioassays for carcinogenicity in rats and mice. A crucial element for assessing the predictive value of rodent thyroid tumors for human cancer hazard is whether data are adequate to exclude a genotoxic mode of action. These tumors are readily induced by many genotoxic carcinogens, but they may also be induced by virtually any nongenotoxic goitrogen in these rodent species. In this respect rodents and humans are quite different. Human thyroid cancers are not exactly comparable to the follicular cell tumors of rats and mice, and no nonradioactive chemical is known to cause these cancers in humans. The only clearly established cause of thyroid cancers in h-mans is ionizing radiation, especially in childhood (Ron 1996).

Occupational exposures to EBDCs cannot be simply equated to exposure to ETU. Occupational exposure to EBDCs entails exposures to the parent compound(s) plus other ingredients of the working formulations used in agriculture, as well as to endogenously formed ETU and other metabolites, and is not identical to environmental exposure to ETU per se. The 1997 study by Steenland et al. concerns a group of workers using a mixture of different pesticides, such as EBDC fungicides, organophosphates (in "a typical mixture" up to 48% by weight), plant-regulating substances, and foliar nutrients (Steenland et al. 1997). As the authors themselves indicate, this paper reported on a single field study with limited sample size; the results are limited to subclinical outcomes (all thyroid hormone data being within the normal range); and the data are of borderline statistical significance and should be interpreted with caution. The working group for IARC Monograph Volume 79 (2001) did justice to the paper by mentioning it as they did.

Steenland's assertion that mechanistic information has been used more often by monograph working groups to reach lower overall evaluations of carcinogenicity--to "downgrade" rather than "upgrade"--is incorrect. Of the 888 overall evaluations of carcinogenicity made since 1972, only a small fraction have been based on what the monographs refer to as "other relevant data," including mechanisms of carcinogenicity. "Upgrades" include 5 from Group 2A to Group 1; 38 from Group 2B to Group 2A; and 6 from Group 3 to Group 2B, a total of 49. Only 8 substances--< 1% of the total--are "downgrades" from Group 2B to Group 3 on the basis of mechanistic information, and only 3 of these substances are thyrotropic chemicals. Anyone can go to the lists of evaluations that are given on the monographs website (IARC 2003) and confirm this. Overall evaluations that rely in part on "other relevant data" bear a notation to that effect.

The authors declare they have no conflict of interest.

Robert A. Baan

Jerry M. Rice *

IARC Monographs Programme

International Agency for Research on Cancer

Lyon, France

E-mail: [e-mail]

* Current address: Chevy Chase, Maryland

REFERENCES

Capen CC, Dybing E, Rice JM, Wilbourn JD, eds. 1999. Species Differences in Thyroid, Kidney and Urinary Bladder Carcinogenesis. IARC Sci Publ 147.

IARC. 1992. Preamble. IARC Monogr Eval Carcinog Risks Hum 54:13-32.

IARC. 2001. Ethylene thiourea. IARC Monogr Eval Carcinog Risks Hum 79:659-701.

IARC. 2003. IARC Monographs Programme on the Evaluation of Carcinogenic Risks to Humans. Available: http:// monographs.iarc.fr [accessed 31 March 2003].

Ron E. 1996. Thyroid cancer. In: Cancer Epidemiology and Prevention (Schottenfeld D, Fraumeni JF Jr, eds). 2nd ed. New York, Oxford:Oxford University Press, 1000-1021.

Steenland K, Cedillo L, Tucker J, Hines C, Sorensen K, Deddens J, et al. 1997. Thyroid hormones and cytogenetic outcomes in backpack sprayers using EBDC fungicides in Mexico. Environ Health Perspect 105:1126-1130.