Non-relevance of acute dermal toxicity testing for assessing human health protection in the regulatory decision-making for agrochemical formulated products.

Compared to oral toxicity tests, dermal toxicity tests offer little or no additional scientific information or public health protection for agrochemical-formulated products (US EPA, 2016). Based on that, a retrospective analysis of the results of acute oral and dermal LD50 studies of agrochemical products registered in Brazil was carried out by the Technical Group on Toxicological Risk Assessment (GT-ART) of the Brazilian Crop Protection Association (ANDEF). The data were obtained from 6 agrochemical industries that are associated to ANDEF, following these considerations: only rat studies were selected; only paired studies were chosen; only studies performed with top doses ≥2,000 mg/kg were selected; biological products were excluded. The dataset includes 342 formulated products in 21 formulation types. Among these 342 formulated products, 228 have a single active ingredient, 107 have 2 and 7 have 3 or more. The comparison of acute oral to dermal toxicity studies of agrochemical-formulated products registered in Brazil corroborates the United States Environmental Protection Agency (US EPA) conclusion on waiving acute dermal toxicity tests, which will result in avoiding unnecessary use of time and resources, data generation costs and animal testing.

Dose and temporal effects on gene expression profiles of urothelial cells from rats exposed to diuron.

Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a substituted urea herbicide that at high dietary levels (2500 ppm) induces rat urinary bladder hyperplasia after 20 weeks of exposure and neoplasia after 2 years. The effects on the urothelium after short-term exposure have not been described. The present 7-day study evaluated the dose-dependency of urothelial alterations in the urinary bladder using light microscopy, scanning electron microscopy, and genome-wide transcriptional profiling. Male Wistar rats were fed 0, 125, 500, 2500 ppm diuron for 7 days. The urinary bladder and isolated urothelial cells of these animals were processed for microscopic examination and gene expression profiling, respectively. No significant treatment-related morphologic effects were observed. The number of differentially expressed genes (DEGs) in the exposed groups increased with diuron levels. Diuron-altered genes involved in cell-to-cell interactions and tissue organization were identified in all treatment groups. After 7 days of diuron exposure, transcriptional responses were observed in the urothelium in the absence of clear morphologic changes. These morphological findings are different from those observed in a previous study in which 20 weeks of diuron exposure was associated with simple hyperplasia secondary to the persistent cytotoxicity and necrosis associated with continuous cellular regeneration. Comparison of the gene expression profiles of rats exposed to the 2500 ppm carcinogenic diuron dose for 7 days versus 20 weeks revealed few similarities between these two time points at the gene or pathway level. Taken together, these data provide insight into the dose- and temporal-dependent morphological and transcriptional changes associated with diuron exposure that may lead to the development of tumors in the rat urinary bladder.

STEAP1 protein overexpression is an independent marker for biochemical recurrence in prostate carcinoma.

AIMS: To investigate the prognostic value of expression levels of the genes STEAP1 and STEAP2, and of STEAP1 protein, in prostate carcinomas (PCa). METHODS AND RESULTS: STEAP1 and STEAP2 transcript levels were evaluated by RT-qPCR in samples from 35 PCa, 24 adjacent non-neoplastic prostate (AdjP) tissues, five cases of benign prostatic hyperplasia (BPH), and two histologically normal prostates (N). STEAP1 expression was assessed by immunohistochemistry in samples from 198 PCa, 76 AdjP, 22 BPH, and two N. The findings were compared with clinical and pathological parameters and patient outcome. STEAP1 and STEAP2 transcript analysis showed no differences between the groups tested. Although not significant, higher STEAP1 mRNA levels were detected in tumours with high Gleason scores and in patients who presented with biochemical recurrence (BCR). STEAP1 overexpression was detected in PCa, and was significantly associated with high-grade Gleason scores, seminal vesicle invasion, BCR, and worse outcome (metastasis or PCa-specific death). STEAP1 overexpression was significantly associated with shorter BCR-free survival. Multivariate analysis revealed that STEAP1 is an independent marker for BCR. CONCLUSIONS: These findings provide evidence that STEAP1 is a biomarker of worse prognosis in PCa patients.