Fumigants: Toxicology and Development of Acute Reference Values for Methyl Bromide, Chloropicrin, and Methyl Iodide
Hazard identification starts with the review of available pharmacokinetic and toxicology information, composed of published toxicity studies as well as studies conducted under the testing guidelines as required for registration . It identifies toxicologically significant endpoints from laboratory animal or human studies. These endpoints are categorized by exposure duration, matching those established in the exposure assessment for worker and nonwork exposure scenarios. The durations are typically acute (single day), short, and intermediate term (1 day to 6 months), long term (>6 months), and for a lifetime. On a daily basis, the USEPA standard exposure durations are 8 hours for workers and bystanders and 24 hours for residents. Thus, different reference values are determined for these two exposure durations. Dose-response assessment is conducted to establish the point of departure (POD) for relevant toxicity endpoint and durations. The POD is the beginning point for the low-dose extrapolation. It can be the highest dose that did not cause any toxicological effect, known as no-observed-effect level (NOEL) or no-observed-adverse-effect level (NOAEL), or a lower-bound benchmark dose (BMDL) derived from dose-response models such as those in the USEPA benchmark dose software . The PODs, along with extrapolation factors, are used to calculate the reference values, as indicated in Eq. 9.1. The HEC is the result after the POD was adjusted for intake, exposure duration, and UFs. POD TAF 1UF 1UF 1UF 1UF = RefereHEC PK PD H Additional¥ ¥ ¥ ¥ ¥ nce concentration (9.1)where POD = point of departure, TAF = time amortization factor, UF = uncertainty factor, PK = pharmacokinetic, PD = pharmacodynamics, H = Human, and HEC = human equivalent concentration. In this equation, the POD is the dose, NOEL or BMDL, associated with the most sensitive endpoint for the duration of concern. The time amortization factor (TAF) is needed when the duration of exposure in a toxicity study is different than that for actual human exposure. There are two interspecies UFs, one for pharmacokinetic (UFPK) and the other for pharmacodynamics (UFPD). When the POD is for an effect observed in a laboratory animal study, the assumption is that humans would be at least as sensitive as the most sensitive laboratory animal species tested, with additional human variability,
to the toxicity of the pesticide. The conventional approach is to reduce the POD by these interspecies UFs, which are generally each a factor of √10, with the total equal to a value of 10. The intraspecies UF (UFH) accounts for difference in the effects of the chemical in the human population. The assumption is that there is a tenfold variation in the response. This factor may be eliminated if the study population included sensitive individuals. An additional UF (UFAdditional) is applied when toxicology or exposure database is considered inadequate. This factor, generally 3 or 10, has been included to address the potential toxicity, such as developmental neurotoxicity, where there is no or inadequate data. The TAF and UFPK terms in Eq. 9.1 can be modified by information regarding the disposition of the pesticide in laboratory animals. In the USEPA risk assessment for methyl bromide, the UFPK term was replaced by a dosimetric adjustment factor . This dosimetric factor takes into consideration the physiochemical properties of the inhaled compound as well as the type of toxicity observed (systemic effect or port of entry effect), and pharmacokinetic differences between laboratory animals and human. For systemic effects from inhaled gases, the factor is the regional gas dose ratio (RGDR). It is defined as the ratio of the blood:gas partition coefficient of the chemical in the test species compared to humans. The RGDR is often a value of 1, a default value when the chemical blood:gas partition coefficients are unknown, or when the value for laboratory animal is greater than that for human. The USEPA analysis of available data showed that the RGDRs were “comparable or slightly higher than 1.” For the portal-of-entry effect, such as rhinitis, the effect is produced at the tissue or organ of first contact. The RGDR is related to the minute volume and surface area of the test species compared to that for human. For inhaled particulate aerosols, the dosimetric adjustment factor is the regional deposited dose ratio (RDDR). This factor takes into consideration the particulate diameter (mass median aerodynamic diameter, MMAD) and the geometric standard deviation. The HEC can be determined by physiologically based pharmacokinetic (PBPK) modeling, as will be discussed for methyl iodide. PBPK modeling requires additional data to determine the internal dose metric and mode of action that leads to the toxicity endpoint of concern. The selection of the appropriate dose metric is a key element to establishing a dose-response relationship in PBPK modeling .