Rethinking chronic toxicity and carcinogenicity assessment for agrochemicals project (ReCAAP): A reporting framework to support a weight of evidence safety assessment without long-term rodent bioassays.

Rodent cancer bioassays have been long-required studies for regulatory assessment of human cancer hazard and risk. These studies use hundreds of animals, are resource intensive, and certain aspects of these studies have limited human relevance. The past 10 years have seen an exponential growth of new technologies with the potential to effectively evaluate human cancer hazard and risk while reducing, refining, or replacing animal use.

Implementing a globally harmonized risk assessment-based approach for regulatory decision-making of crop protection products.

A global, harmonized evaluation system for crop protection chemicals based on exposure and risk will improve the ability to inform risk management decisions and better support innovation. This would be achieved through harmonized risk assessment-based regulatory decision-making realized through the application of the best available science, via integration of new methods and traditional data to create tailored exposure-driven risk assessments. A requirement to achieve success is a structure that encourages direct communication between the regulatory community and the regulated industry, which would enable a more rapid incorporation of new technologies and advancing science.

Minimum datasets to establish a CAR-mediated mode of action for rodent liver tumors.

Methods for investigating the Mode of Action (MoA) for rodent liver tumors via constitutive androstane receptor (CAR) activation are outlined here, based on current scientific knowledge about CAR and feedback from regulatory agencies globally. The key events (i.e.

Assessment of in vitro human dermal absorption studies on pesticides to determine default values, opportunities for read-across and influence of dilution on absorption.

Dermal absorption is an integral part of non-dietary human safety risk assessments for agrochemicals. Typically, dermal absorption data for agrochemical active substances are generated from the undiluted formulation concentrate and its spray dilutions. European Food Safety Authority (EFSA) guidance, which combines highly conservative default values, very limited opportunities for read-across from existing data and other overly conservative conclusions, was the driver for this assessment.

Diuron-induced rat bladder epithelial cytotoxicity.

Diuron, a substituted urea herbicide, is carcinogenic to the rat urinary bladder at high dietary levels (2500 ppm). To further elucidate the mode of action, this study aimed to determine the time course and sequence of bladder cytotoxic and proliferative changes induced by diuron treatment of male Wistar rats. Rats were randomized into two groups (control and 2500 ppm diuron) and treated for 28 days.

Current and future use of genomics data in toxicology: opportunities and challenges for regulatory applications.

Toxicogenomics is the application of toxicology, genetics, molecular biology and environmental health to describe the response of organisms to environmental stimuli. The field of toxicogenomics has developed over the past 15 years mainly due to advances in toxicology, molecular genetics and cell biology. Its prospective use to resolve crucial data gaps and data inconsistencies could improve risk assessment by providing additional data to increase the understanding of mechanisms and modes of action (MOA) and enhance the reliability of dose-response extrapolation.

Age-dependent skin tumorigenesis and transgene expression in the Tg.AC (v-Ha-ras) transgenic mouse.

Transgenic Tg.AC (v-Ha-ras ) mice develop skin tumors in response to specific carcinogens and tumor promoters. The Tg.

A farnesyl transferase inhibitor suppresses TPA-mediated skin tumor development without altering hyperplasia in the ras transgenic Tg.AC mouse.

The Tg.AC mouse carries an activated v-Ha-ras oncogene fused to an embryonic zeta-globin promoter and develops cutaneous papillomas in response to specific chemicals, full thickness wounding, and ultraviolet radiation. Papilloma development in these mice has been suggested to be dependent upon activation of ras transgene expression, thus providing a potential model for studying ras-inhibitory compounds.

Morphological characterization of spindle cell tumors induced in transgenic Tg.AC mouse skin.

Transgenic Tg.AC mice carry a v-Ha-ras coding region flanked by a zeta-globin promoter and an SV40 polyadenylation signal sequence. These mice respond to carcinogens by developing epidermal papillomas.

Regression and progression characteristics of papillomas induced by chrysarobin in SENCAR mice.

The present study was designed to test the effects of a free radical generating tumor promoter, chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone), on the growth and progression of papillomas generated in the skin of SENCAR mice. In the first set of experiments, papillomas were generated by initiation with 6.4 microg of 7,12-dimethylbenz[a]anthracene (DMBA) followed by promotion with once-weekly applications of 52.

The effects of calcium antagonists on anthrone skin tumor promotion and promoter-related effects in SENCAR mice.

The present study investigated a possible role for Ca2+ in skin tumor promotion by anthrones. This was accomplished by testing the effects of two Ca2+ antagonists, verapamil and 3,4,5-trimethoxybenzoic acid 8-(diethylamino) octyl ester (TMB-8), on tumor promotion and promoter-related effects induced by the anthrone chrysarobin in SENCAR mice. Verapamil and TMB-8 both effectively inhibited epidermal ornithine decarboxylase (ODC) induction by a single application of chrysarobin.

Inhibition of chrysarobin skin tumor promotion in SENCAR mice by antioxidants.

The present study was designed to further investigate the role of reactive oxygen species in the mechanism of action of anthrone tumor promoters. To accomplish this, the effects of several antioxidants on the induction of epidermal ornithine decarboxylase (ODC) activity, epidermal hyperplasia, skin edema, and skin tumor promotion by chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone) were tested. Ascorbyl palmitate (AP), given 5 min prior to the promoter at 1 and 4 mumol doses, effectively inhibited the induction of ODC activity (28% and 59%, respectively) by 220 nmol of chrysarobin.

Occurrence of thymic lymphoma in carcinogenesis bioassay specimens of the Japanese medaka (Oryzias latipes).

Multiple cases of thymic lymphoma were diagnosed in bioassay specimens of Japanese medaka (Oryzias latipes), a small fish species. Lymphoma in chemically exposed specimens was not clearly related to specific compounds, dose, or sex. Multiple cases of lymphoma occurred in three specimens held in one aquarium and in two specimens in two other aquaria, suggesting the possibility of horizontal transmission.