Reto Engler

Toxicological considerations for protein components of biological pesticide products

The toxicity of protein components of microbial pesticide products is evaluated at EPA by requiring that pesticide manufacturers conduct a thorough taxonomic evaluation of the active microbial ingredient. The requirement for acute toxicity testing by dosing laboratory animals with the active microbial ingredient and with fermentation growth medium materials provides additional information on the toxicity of protein components of microbial pesticides. The potential for toxicity from proteins associated with contaminating organisms is addressed by use of appropriate quality control procedures to minimize or prevent growth of contaminants and by screening of fermentation batches for known human/mammalian pathogens. These considerations also would apply to any biochemical pesticide that is formed via the growth of a microorganism. If a protein itself is intended for commercial use as an active pesticide ingredient, acute exposure studies and in vitro digestibility studies could be done to answer potential concerns regarding toxicity.

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 EPAs 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 agencys 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.

Evaluation of the carcinogenic potential of pesticides: 1. Acifluorfen

The Health Effects Division of the Office of Pesticide Programs evaluates the carcinogenic properties of pesticides by a consensus peer review process in which all available biological information on a compound is evaluated according to EPAs guidelines for cancer risk assessment. In many cases, pesticides are also evaluated by an external group of accomplished scientists who comprise the Agencys Scientific Advisory Panel. The herbicide acifluorfen was evaluated by these processes and was classified as a Category B2 (probable human) carcinogen based upon evidence of an increased incidence of malignant, or combined benign and malignant, tumors in multiple experiments involving two different strains of mice. The compound produced benign and malignant liver tumors in male and female B6C3F1 mice and in female CD1 mice. Stomach papillomas were also observed in male and female B6C3F1 mice. Acifluorfen was mutagenic in bacteria and yeast, but not in mammalian cell systems. In addition, acifluorfen is structurally related to eight other diphenyl ether pesticides, all of which evoke liver tumours in mice or rats. The data were found to be sufficient to quantify human risk to acifluorfen.

REGULATION OF MICROBIAL PESTICIDES

For any pesticide to move in interstate commerce in the United States, it must be registered by the United States Environmental Protection Agency (EPA). Any proposed use that can reasonably be expected to result in residues on food or feed must be supported by a tolerance or exemption under the Food, Drug, and Cosmetic Act. Establishment of tolerances under this statute is also the responsibility of EPA. Before EPA will register the pesticide, it must be furnished with acceptable evidence of ingredients, efficacy in achieving the results intended, safety to man and his environment, analytical methods suitable for determination of the ingredients, and a suitable label that describes ingredients, methods of use, and any necessary precautionary statements. In addition, if a tolerance is needed, data must be provided that show the level of residue expected to remain on food or feed and the proposed tolerance limit. Tolerances and not set at a greater level than that needed to cover the expected residue and never greater than the level needed to be safe to man, with appropriate safety factors. A temporary tolerance or temporary exemption may be requested. These are generally granted for a period of one year and are concurrent with a temporary permit that covers limited experimental use of the pesticide. This permit allows the petitioner to test the pesticide on a relatively large scale. The temporary tolerance permits the treated crops to be marketed legally. Because exposure to consumers will be quite limited, the toxicity and residue data required for granting of a temporary tolerance is generally less than that for a permanent tolerance and registration. This depends on several factors that include the raw agricultural commodity to be treated (Is it a major food item?), the total acreage to be treated, the residue level expected, the potential for transfer to meat, milk, poultry or eggs, and the results of preliminary toxicity studies. A temporary experimental permit may be granted without a temporary tolerance (or exemption) if no food or feed crops are involved. Also, experimental permits for limited quantities may be granted for use on food crops, with a condition that the treated crop will be destroyed or used only for laboratory purposes. Obviously, these requirements were developed with inanimate pesticides in mind. Nevertheless, the applicable federal statutes do not distinguish between living and nonliving pesticides, and therefore the EPA has the responsibility for adapting these requirements for use with microbial pesticides. This is not easy to do and has resulted in considerable deliberateness in deciding what type of evidence should be required. EPA and its predecessor agencies have been quite concerned with this matter. We recognize the desirability of substituting more natural control methods (such as microbial pesticides) for the highly persistent and broad-spectrum chemicals now in use, including those that may be acutely toxic to humans, animals, or plants, even if these chemicals are not persistent. We also recognize that the introduction of “desirable” organisms into this country from abroad has sometimes had serious and unforeseen adverse effects

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 EPAs 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.

Review of the Office of Pesticide Program's current toxicology guidelines for the testing of pesticides.

Prior to the registration or reregistration of a chemical, the Environmental Protection Agency must identify the chemicals hazard and determine whether it will cause unreasonable adverse effects on man and the environment. In the process of making this determination, the Agency reviews: (1) all data submitted by the registrant to support the effectivenessand safety of the chemical, (2) published reports; studies from the open literature, (3) unpublished reports or studies which bear on the issues at hand, and (4) the chemicals general and environmental chemistry relationship to possible human and domestic animal exposure. The data requirements for registration of pesticide products are specified in 40 CFR Part 158. The Agencys recommendations on test protocols and the reporting and evaluation of toxicology data, described below, are categorized in the opp Pesticide Assessment Guidelines, Subdivision F.