Evaluation of potential human health effects associated with the agricultural uses of 1,3-D: Spatial and temporal stochastic risk analysis.

Dow AgroSciences (DAS) markets and sells 1,3-Dichloropropene (1,3-D), the active ingredient in Telone®, which is used as a pre-plant soil fumigant nematicide in economically important crops in California. 1,3-D has been regulated as a "probable human carcinogen" and the California Department of Pesticide Regulation limits use of 1,3-D based on human health risk assessments for bystanders. This paper presents a risk characterization for bystanders based on advances in the assessment of both exposure and hazard. The revised bystander risk assessment incorporates significant advances: 1) new data on residency duration and mobility in communities where 1,3-D is in high demand; 2) new information on spatial and temporal concentrations of 1,3-D in air based on multi-year modeling using a validated model; and 3) a new stochastic spatial and temporal model of long-term exposures. Predicted distributions of long-term, chronic exposures indicate that current, and anticipated uses of 1,3-D would result in lifetime average daily doses lower than 0.002mg/kg/d, a dose associated with theoretical lifetime excess cancer risk of <10(-5) to >95% of the local population based on a non-threshold risk assessment approach. Additionally, examination of 1,3-D toxicity studies including new chronic toxicity data and mechanism of action supports the use of a non-linear, threshold based risk assessment approach. The estimated maximum annual average daily dose of <0.0016mg/kg/d derived from the updated exposure assessment was then compared with a threshold point of departure. The calculated margin of exposure is >1000-fold, a clear indication of acceptable risk for human health. In summary, the best available science supports 1,3-D's threshold nature of hazard and the revised exposure assessment supports that current agricultural uses of 1,3-D are associated with reasonable certainty of no harm, i.e., estimated long-term exposures pose insignificant health risks to bystanders even when the non-threshold approach is assumed.

Cyphenothrin Flea and Tick Squeeze-On for Dogs: Evaluation of Potential Health Risks Based on the Results of Observational Biological Monitoring.

An observational biomonitoring study was conducted involving adults and children in households that purchased and applied a cyphenothrin-containing spot-on product for dogs as part of their normal pet care practices. The 3- to 6-yr-old children had greater exposure than the adult applicators in the same house, 3.8 and 0.6 µg/kg body weight, respectively. The mean measured values in children were 13-fold lower than those estimated using the U.S. Environmental Protection Agency (EPA) current standard operating procedures (SOP) for pet products (assuming 5% dermal absorption), although the maximum absorbed dosage of one child on one day was equivalent to the default value derived from the SOPs. With regard to potential human health risks, it can be concluded that despite the inherent conservatism in both the exposure and toxicology data, the margins of exposure (MOE) were consistently greater than 100 for average, 95th percentile, and maximum exposures. More specifically, the results of this study demonstrated that the MOE were consistently greater than 1,000 for mean exposures and exceeded 100 for 95th percentile and maximum measured exposures, which clearly indicates a reasonable certainty of no harm when using the cyphenothrin spot-on products. It is also noteworthy that Sergeant's spot-on products containing cyphenothrin currently sold in the United States have lower weight percentages of active ingredient and lower applied amounts than those used by all but two of the participant households in this study.

Effects of 17 beta-estradiol exposure on Xenopus laevis gonadal histopathology.

The natural estrogen 17 beta-estradiol (E2) is a potential environmental contaminant commonly employed as a positive control substance in bioassays involving estrogenic effects. The aquatic anuran Xenopus laevis is a frequent subject of reproductive endocrine disruptor research; however, histopathological investigations have tended to be less than comprehensive. Consequently, a study was designed to characterize gross and microscopic changes in the gonads of X. laevis as a result of E2 exposure. Additional goals of this study, which consisted of three separate experiments, included the standardization of diagnostic terminology and criteria, the validation of statistical methodology, and the establishment of a half maximal effective concentration (EC50) for E2 as defined by an approximately 50% conversion of presumptive genotypic males to phenotypic females. In the first experiment, frogs were exposed to nominal concentrations of 0, 0.2, 1.5, or 6.0 microg/L E2. From these experimental results and those of a subsequent range finding trial, the EC50 for E2 was determined to be approximately 0.2 microg/L. This E2 concentration was utilized in the other two experiments, which were performed at different facilities to confirm the reproducibility of results. Experiments were conducted according to Good Laboratory Practice guidelines, and the histopathologic evaluations were peer reviewed by an independent pathologist. Among the three trials, the histopathological findings that were strongly associated with E2-exposure (p<0.001 to 0.0001) included an increase in the proportion of phenotypic females, mixed sex, dilated testis tubules, dividing gonocytes in the testis, and dilated ovarian cavities in phenotypic ovaries. A comparison of the gross and microscopic evaluations suggested that some morphologic changes in the gonads may potentially be missed if studies rely entirely on macroscopic assessment.

Development, standardization and refinement of procedures for evaluating effects of endocrine active compounds on development and sexual differentiation of Xenopus laevis.

Xenopus laevis has been introduced as a model to study effects of endocrine-active compounds (EAC) on development and sexual differentiation. However, variable and inconsistent data have raised questions about the reliability of the test methods applied. The current study was conducted in two laboratories to develop, refine, and standardize procedures and protocols. Larvae were exposed in flow-through systems to 17beta-estradiol (E2), at concentrations from 0.2 to 6.0 microg E2 L(-1) in Experiment 1A, and 0.015 to 2.0 microg E2 L(-1) in Experiment 1B. In both studies survival (92%, 99%) and percentage of animals that completed metamorphosis (97%, 99%) indicated reproducible biological performance. Furthermore, minor variations in husbandry led to significant differences in snout-to-vent length, weight, and gonad size. In Experiment 1A, almost complete feminization occurred in all E2 treatment groups whereas a concentration response was observed in Experiment 1B resulting in an EC(50) of 0.12 microg E2 L(-1). The final verified protocol is suitable for determining effects of EAC on development and sexual differentiation in X. laevis.

Mortality partitions and their relevance to research on senescence.

The reasons for classifying causes of death into aggregate groups are discussed and the impact of mortality partitions on analyses of mortality is described. Special emphasis is given to a mortality partition that distinguishes between intrinsic causes of death that arise primarily from the failure of biological processes that originate within an organism, and extrinsic causes of death that are primarily imposed on the organism by outside forces. Examples involving mortality data for mice, dogs, and humans are used to illustrate how this mortality partition infuses biological reasoning into mathematical models used to analyze and predict senescent-determined mortality, enhances the information content of the mortality schedules generated from these models, improves mortality comparisons between populations within species separated by time or geographic location, and provides a logical pathology endpoint for making interspecies comparisons of mortality. By bridging biology and the statistics of mortality, a mortality partition based on intrinsic and extrinsic causes of death provides both structure and direction for research on senescent-determined mortality.

Statistical inferences about the mechanism of action in carcinogenicity studies.

An innovative approach to dose-response modeling provides statistical insight into the relative likelihood of different mechanisms of action in cancer dose-response studies. Two illustrative examples are given based on time-to-tumor data on mammary fibroadenoma and adenocarcinoma in female Sprague-Dawley rats using 34 different dose metrics. The likelihood for the study outcome was calculated for each dose metric and compared with the background likelihood using a likelihood-ratio test. In the first example, fibroadenomas were strongly related to the presence or absence of mammary secretory activity, galactoceles, pituitary tumors, and abnormal diestrous days in weeks 1 to 26. Adenocarcinomas were the most strongly related to the number and percentage of abnormal estrous days. In these examples, the usual dose metric based on the dietary concentration of the pesticide had some explanatory ability but not nearly as much as the dose metrics more directly related to hormonal mechanisms of action.