Endocrine modulators: risk characterization and assessment.

Over the last several years, information has been accumulating that suggests that adverse effects are being induced in certain wildlife species, and perhaps also in humans, as a consequence of exposure to man-made chemicals that have been released into the environment. Many of these effects have been attributed to interactions with various hormone systems in endocrine tissues. Most often the effects observed have been effects on reproduction and development, although there are also (often conflicting) data regarding an association between exposure and certain kinds of cancer, particularly cancers of reproductive tissues such as breast and testis; effects on the immune system have also been noted. The substances to which these attributes have been ascribed have come to be known as "endocrine modulators" or "endocrine disruptors." The full nature and scope of the "problem" of endocrine modulators/disruptors is currently a matter of great debate, both within and outside of the scientific community. Regulatory authorities around the world are being asked what their position is on this issue and what, if any, regulatory strategies they are developing to address the problem. In many cases, because of the nature of the legislation under which governments manage chemicals, regulatory decisions must be informed by risk assessment. This presentation will describe the general approach to the risk assessment of endocrine modulators/disruptors as practiced by the US government, with particular focus on the current practices/policies of the US Environmental Protection Agency.

Endocrine disruptor risk characterization: an EPA perspective.

The characterization of risk to endocrine-disruptive agents may prove to be one of the greatest challenges that the risk assessment/regulatory community has ever faced. Why is this so? The endocrine system is actually many systems, having complex interactions and interdependencies. Normal endocrine function is often dependent on cyclical events, rather than steady-state. Timing is everything, as evidenced by significant differences in adverse outcome as a function of age and stage of development. Further, the consequences of concomitant exposures to endocrine-active substances in the diet or as therapeutic agents are poorly understood. So, how should risk characterization to these agents be approached? This presentation will include the description of current practices for addressing hormonally mediated cancer and noncancer effects and offer speculation on modifications to these approaches that might be necessary as our knowledge of this area increases.

Impact of the Delaney Clause in the EPA.

The U.S. Environmental Protection Agency serves as the lead agency of the Federal government for the regulation of pesticide use in the United States. Regulatory responsibilities are mandated in the Federal Insecticide Fungicide and Rodenticide Act (FIFRA) and several sections of the Federal Food Drug and Cosmetic Act (FFDCA). In order for a pesticide to be used in the U.S., it must either be granted a full registration under Section 3, or offered special consideration under Section 18 or 24 of FIFRA. Tolerances (maximum allowable residue limits) for pesticides to be used on agricultural commodities meant for human consumption or animal feed are established under Sections 408 and/or 409 of FFDCA. This presentation will describe the underlying conflict between Section 409 of FFDCA and both Section 408 and FIFRA, the recommendations made by the National Academy of Sciences in its 1987 publication Regulating Pesticides in Food--The Delaney Paradox, EPA's attempts to implement these recommendations, the true impact of "Delaney" on the ability of EPA to grant tolerances on raw or processed foods for chemicals determined to meet the "induce cancer" criterion and the status of legislation designed to "fix" Delaney.

Evaluation of the carcinogenic potential of pesticides. 4. Chloroalkylthiodicarboximide compounds with fungicidal activity.

The Health Effects Division of the Office of Pesticide Programs (OPP) assessed the carcinogenic potential of three structurally related chloroalkylthiodicarboximide fungicides using a consensus peer review process and EPA's 1986 guidelines for cancer risk assessment. All of the fungicides were categorized as Group B2 (probable human) carcinogens based upon findings of an increased incidence of malignant tumors, or combined malignant and benign tumors, in multiple experiments involving different strains of mice and rats. The primary sites of tumor formation with the chloroalkylthiodicarboximide fungicides in male and/or female mice (CD-1 and B6C3F1) were the gastrointestinal tract (captan, folpet, and captafol), the lymph system (folpet and captafol), and the vascular system (captafol). The main sites of tumor formation in rats of one or both sexes (CR CD, Wistar, or F344 strains) were the kidney (Captan and captafol), uterus (captan), mammary gland and liver (captafol). In addition, positive trends for thyroid, testicular, mammary gland, and lymph node tumors were observed with folpet in the same strains of rats. All three of the compounds exhibited positive mutagenic activity in a variety of in vitro short-term tests for gene mutation, DNA repair, and chromosomal aberrations in prokaryotic and eukaryotic cells, but were not genotoxic in available studies performed under in vivo conditions. The assessment of human cancer risk for captan, folpet, and captafol was made using low-dose extrapolation models.

Evaluation of the carcinogenic potential of pesticides. 3. Aliette.

Aliette, a fungicide compound, was evaluated for carcinogenic potential by the Health Effects Division of the Office of Pesticide Programs using a consensus peer review process and EPA's guidelines for risk assessment. Aliette was categorized as a group C (possible human) carcinogen based upon evidence of an increased incidence of combined benign and malignant urinary bladder tumors in a single study involving male Charles River (CR) CD rats. The bladder tumors occurred only at the unusually high top dose level of aliette that was tested (40,000/30,000 ppm). The compound was not carcinogenic in female CR-CD rats in the same study, or in CD-1 mice of either sex in a second study. Monosodium phosphite, the main urinary metabolite of aliette, was also not carcinogenic in male or female CR-CD rats. Aliette was not demonstrated to be genotoxic. No structural analogues of aliette were identified. The mechanism of action for the production of bladder tumors was not identified; however, it did not appear to involve a genotoxic effect, a carcinogenic effect of metabolites, or the formation of renal stones. The data were not found to be sufficient to quantify human cancer risk from aliette.

Evaluation of the carcinogenic potential of pesticides. 2. Methidathion.

The carcinogen potential of methidathion, a dimethoxyorganic phosphorus pesticide and cholinesterase inhibitor, was evaluated by the Health Effects Division of the Office of Pesticide Programs using a consensus peer review process and the EPA's guidelines for risk assessment. Methidathion was categorized as a Group C (possible human) carcinogen based upon evidence of an increased incidence of benign and malignant hepatocellular tumors, alone and in combination, in a single study involving male Chr-CD-1 mice. The compound was not carcinogenic in female Chr-CD-1 mice in the same study or in Sprague-Dawley rats of either sex in a second study. Methidathion was not genotoxic in a variety of in vitro or in vivo tests designed to detect DNA damage, chromosome aberrations, gene mutations, and sister chromatid exchange. Although methidathion was identified as being structurally similar to two other organophosphate insecticides, prothidathion and lythidathion, no toxicological data were available on either of these agents for comparative purposes. The biological information on methidathion was reviewed by the agency's FIFRA Scientific Advisory Panel who agreed with the category C designation for methidathion. The data were not found to be sufficient to quantify human risk to methidathion.