A species specific metabolism leading to male rat reprotoxicity of Cyclamen aldehyde: in vivo and in vitro evaluation.

Cyclamen aldehyde (CA; 3-(4-isopropylphenyl)-2-methylpropanal) is a widely used fragrance material. Repeated dose studies in rats revealed adverse effects on sperm maturation. Here we review all the mechanistic and in vivo evidence, to determine relevancy to human health. The effect on spermatogenesis appears to be linked to the metabolite p-isopropyl-benzoic acid (p-iPBA). Studies in rat, rabbit and human suspended hepatocytes indicated species differences with p-iPBA detected in rat hepatocytes only. In plated rat hepatocytes, p-iPBA is conjugated to Coenzyme A (CoA) and p-iPBA-CoA accumulates to stable levels over 22 h. In vitro accumulation of CoA conjugates is a metabolic hallmark correlated to male rat reproductive toxicity for related compounds. p-iPBA-CoA is formed in vivo in liver and testes of rats dosed with CA. In plated rabbit and human hepatocytes p-iPBA-CoA doesn't accumulate. Correlating to this lack of metabolite accumulation, no effects of CA on spermatogenesis were observed in a rabbit in vivo study. A species specific metabolic fate linked to CA toxicity in male rats is postulated which appears not relevant to the rabbit as non-responder species. Lack of accumulation of p-iPBA-CoA in human hepatocytes indicates that like rabbits, humans are unlikely to be vulnerable to p-iPBA hepatic and testicular toxicity.

Benzoyl-CoA conjugate accumulation as an initiating event for male reprotoxic effects in the rat? Structure-activity analysis, species specificity, and in vivo relevance.

A number of para-substituted benzoic acids (p-BA) and chemicals metabolized to p-BA have been found to confer adverse effects in male rats on sperm viability, motility, and morphology. These effects are putatively associated with the metabolism of p-BA to toxic intermediates. We had shown that p-BA lead to accumulation of high levels of p-alkyl-benzoyl-CoA conjugates in plated primary rat hepatocytes. Here we further investigated the relevance of this metabolic pathway for the reprotoxic effects in rats and rabbits. We extended the structure-activity relationship to a set of 19 chemicals (nine reprotoxic and ten non-reprotoxic) and confirmed a very strong correlation between p-alkyl-benzoyl-CoA accumulation in rat hepatocytes and the toxic outcome. Species specificity was probed by comparing rat, rabbit and human hepatocytes, and p-benzoyl-CoA accumulation was found to be specific to the rat hepatocytes, not occurring in human hepatocytes. There was also very limited accumulation in hepatocytes from rabbits that are a non-responder species in in vivo studies. Tissues of rats treated with 3-(4-isopropylphenyl)-2-methylpropanal were analysed and p-isopropyl-benzoyl-CoA conjugates were detected in the liver and in the testes in animals at toxic doses indicating that the metabolism observed in vitro is relevant to the in vivo situation and the critical metabolite does also occur in the reproductive tissue. These multiple lines of evidence further support benzoyl-CoA accumulation as a key initiating event for a specific group of male reproductive toxicants, and indicate a species-specific effect in the rat.

Cross-sectional study on respiratory morbidity in workers after exposure to synthetic amorphous silica at five German production plants: exposure assessment and exposure estimates.

OBJECTIVES: Synthetic amorphous silicas (SASs) are nanostructured polymorphs of silicon dioxide. We compared two different exposure assessments. METHODS: This study estimated cumulative exposure to inhalable SAS dust in 484 male workers from five German SAS-producing plants. Two procedures (P1 and P2) were applied. P1 was based on an expert assessment. P2 was a multiple exposure assessment (15 scenarios) anchored by a recent measurement series (1375 personal measurements of inhalable SAS dust concentration) and used expert assessments. RESULTS: Cumulative exposure estimates for P1 averaged 56.9 mg/m·yrs (range, 0.1 to 419); for a selected P2 scenario, the mean was 31.8 mg/m·yrs (range, 0.4 to 480), (P < 0.0001). Averages varied between the 15 P2-scenarios from 12.6 to 109.6 mg/m·yrs. Different time trends for SAS concentrations were observed. CONCLUSIONS: Both approaches suffer from considerable uncertainties that need to be considered in epidemiological studies.