Chlorpyrifos (CPF) and diazinon (DZN) are thionophosphorus organophosphate (OP) insecticides; their toxicity is mediated through CYP metabolism to CPF-oxon and DZN-oxon, respectively. Conversely, CYPs also detoxify these OPs to trichloropyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), respectively. In addition, A-esterase (PON1) metabolism of CPF- and DZN-oxon also forms TCP and IMHP. This study evaluated the role intestinal and hepatic metabolism may play in both the activation and detoxification of CPF and DZN in Sprague-Dawley rats. Similar CYP- and PON1-mediated metabolic profiles were demonstrated in microsomes from liver or isolated intestinal enterocytes. The metabolic efficiency was estimated by calculating the psuedo-1st order rate constant from the metabolic constants by dividing Vmax/Km. In enterocyte microsomes, the CYP metabolic efficiency for metabolism to the oxon metabolites was approximately 28-fold greater for CPF than DZN. Compared on a per nmol P450 basis, the Vmax for CPF in enterocytes was approximately 2-3 times higher than in liver microsomes for the production of CPF-oxon and TCP. The Michaelis-Menten rate constant (Km) for the metabolism of CPF to CPF-oxon was comparable in liver and enterocyte microsomes; however, the enterocyte Km for TCP production was higher (indicating a lower affinity). The smaller volume of intestine, lower amount of CYP, and higher Km for TCP in the enterocyte microsomes, resulted in a lower catalytic efficiency (2 and 62 times) than in liver for oxon and TCP. PON1-mediated metabolism of CPF- and DZN-oxon was also demonstrated in liver and enterocyte microsomes. Although PON1 affinity for the substrates was comparable in hepatic and enterocytic microsomes, the Vmax were 48- to 275-fold higher, in the liver. These results suggest that intestinal metabolism may impact the metabolism of CPF and DZN, especially following low-dose oral exposures.

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The primary mechanism of action for organophosphorus (OP) insecticides, like chlorpyrifos and parathion, is to inhibit acetylcholinesterase (AChE) by their oxygenated metabolites (oxons), due to the phosphorylation of the serine hydroxyl group located in the active site of the molecule. The rate of phosphorylation is described by the bimolecular inhibitory rate constant (k(i)), which has been used for quantification of OP inhibitory capacity. It has been proposed that a peripheral binding site exists on the AChE molecule, which, when occupied, reduces the capacity of additional oxon molecules to phosphorylate the active site. The aim of this study was to evaluate the interaction of chlorpyrifos oxon (CPO) and paraoxon (PO) with rat brain AChE to assess the dynamics of AChE inhibition and the potential role of a peripheral binding site. The k(i) values for AChE inhibition determined at oxon concentrations of 1-100 nM were 0.206 +/- 0.018 and 0.0216 nM(-1)h(-1) for CPO and PO, respectively. The spontaneous reactivation rates of the inhibited AChE for CPO and PO were 0.084-0.087 (two determinations) and 0.091 +/- 0.023 h(-1), respectively. In contrast, the k(i) values estimated at a low oxon concentration (1 pM) were approximately 1,000- and 10,000-fold higher than those determined at high CPO and PO concentrations, respectively. At low concentrations, the k(i) estimates were approximately similar for both CPO and PO (150-180 [two determinations] and 300 +/- 180 nM(-1)h(-1), respectively). This implies that, at low concentrations, both oxons exhibited similar inhibitory potency in contrast to the marked difference exhibited at higher concentrations. These results support the potential importance of a secondary peripheral binding site associated with AChE kinetics, particularly at low, environmentally relevant concentrations.

Ethanol-based topical antiseptic hand rubs, commonly referred to as alcohol-based hand sanitizers (ABHS), are routinely used as the standard of care to reduce the presence of viable bacteria on the skin and are an important element of infection control procedures in the healthcare industry. There are no reported indications of safety concerns associated with the use of these products in the workplace. However, the prevalence of such alcohol-based products in healthcare facilities and safety questions raised by the U.S. FDA led us to assess the potential for developmental toxicity under relevant product-use scenarios. Estimates from a physiologically based pharmacokinetic modeling approach suggest that occupational use of alcohol-based topical antiseptics in the healthcare industry can generate low, detectable concentrations of ethanol in blood. This unintended systemic dose probably reflects contributions from both dermal absorption and inhalation of volatilized product. The resulting internal dose is low, even under hypothetical, worst case intensive use assumptions. A significant margin of exposure (MOE) exists compared to demonstrated effect levels for developmental toxicity under worst case use scenarios, and the MOE is even more significant for typical anticipated occupational use patterns. The estimated internal doses of ethanol from topical application of alcohol-based hand sanitizers are also in the range of those associated with consumption of non-alcoholic beverages (i.e., non-alcoholic beer, flavored water, and orange juice), which are considered safe for consumers. Additionally, the estimated internal doses associated with expected exposure scenarios are below or in the range of the expected internal doses associated with the current occupational exposure limit for ethanol set by the Occupational Safety and Health Administration. These results support the conclusion that there is no significant risk of developmental or reproductive toxicity from repeated occupational exposures and high frequency use of ABHSs or surgical scrubs. Overall, the data support the conclusion that alcohol-based hand sanitizer products are safe for their intended use in hand hygiene as a critical infection prevention strategy in healthcare settings.