1,721,023 research outputs found
Genotoxicity in risk assessment : is it time to use a threshold approach?
No full textSubstances that act via a genotoxic mechanism are considered to follow a low dose linear relationship with the absence of a threshold. The discussion on the existence of a threshold for genotoxic (mutagenic and clastogenic) compounds appears sometimes more an academic exercise than of practical use in public health. However, pragmatically, determination of the PoD, i.e. the dose/concentration from which we derive acceptable exposure levels, should be the goal. This will include appropriate dose response data analysis, with statistically defensible methods and use of mechanistic data, and application of adequate uncertainty factors. The best and full use of the quantitative information can be used to analyse dose–response data, and dismiss the binary classification scheme for use in risk assessment and management. Certainly, in areas such as the relationship between the genotoxic and the carcinogenic effect, the appropriate BenchMark Response (BMR) to be used, the relation between effects in target tissues vs those observed in surrogate tissues, and the uncertainty of our measurements there is a need of more solid data. While the simple binary classification scheme can be of some help for screening and prioritization of substances that need further scrutiny, it is not an adequate tool to be used for risk management decisions. The final step of the assessment for guiding management decisions should be quantitative to the extent possible. Accepting the threshold approach on which to base the risk management decisions has significant beneficial economic and societal impact and implications
Biochemical studies on the soluble fraction of hen peripheral nerve: searching the target of promotion of axonopathies
No full textInduction and promotion of delayed polyneuropathy by phosphoroamidates. In vitro and in vivo studies
No full textThe relevance of inhibitor-substrate interactions when measuring neuropathy target esterase inhibition
No full textThe putative target of promotion in whole homogenates and soluble fractions from hen sciatic nerve
No full textThe relationship between isofenphos cholinergic toxicity and the development of polyneuropathy in hens and humans
No full textSpecies differences have been observed between hen and human clinical manifestations of isofenphos toxicities. Hens treated with the insecticide isofenphos (90 mg/kg p.o.) developed severe cholinergic toxicity followed by mild organophosphate-induced delayed polyneuropathy (OPIDP). However, a patient developed severe OPIDP, which was preceded by very mild cholinergic signs, after an attempted suicide with a commercial formulation containing isofenphos and phoxim, an insecticide not causing OPIDP (estimated doses were 500 and 125 mg/kg, respectively). To explain this difference the following hypotheses were tested: (1) phoxim is a promoter of isofenphos-induced OPIDP; (2) whereas neuropathy target esterase (NTE) is thought to be the target of OPIDP, activation of isofenphos by liver microsomes causes the formation of more potent NTE inhibitor(s) in humans than in hens; (3) in contrast to hen NTE, the sensitivity of the human enzyme to such inhibitor(s) is higher than that of acetylcholinesterase (AChE), the target of cholinergic toxicity. Results showed that phoxim (22.5 mg/kg p.o.) was not a promoter of OPIDP in hens and that the ratio AChE inhibition:NTE inhibition by microsome-activated isofenphos was similar for both hen and human enzymes. The schedule of antidotal treatment in hens is the likely explanation for the observed difference from the patient. Peak AChE inhibition was maintained in hen brain up to 6 days after a single dose of isofenphos, suggesting prolonged pharmacokinetics. However, the AChE reactivator pyridine-2-aldoxime (2-PAM) was given to hens before isofenphos and then every 8 h, whereas continuous 2-PAM infusion was provided to the patient. When 2-PAM was given to hens every hour after isofenphos (90 mg/kg p.o.), the birds remained asymptomatic. Since other organophosphates may have a prolonged pharmacokinetics, testing procedures for the potential of these insecticides to cause OPIDP may underestimate the risk for humans
Promotion and protection from an organophosphate induced delayed polyneuropathy (OPIDP) by molinate: biochemical, clinical and morphological studies
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