Friday, May 27, 2005

Human Variability - increased low dose risk

A shallow slope of the exposure response relationship in the observable range in a laboratory bioassay predicts a higher low dose risk; a steep slope a lower low dose risk and thus allows a higher and less protective exposure limit. Increased variability in biological response of the host predicts a shallower exposure response relationship. BrooklynDodger hypothesizes that genetically diverse free living humans show greater variability than genetically homogeneous inbred laboratory housed animals. Therefore, a reference dose established with a dose response relationship in a laboratory study will be underestimate risk in people.

Studies identifying human variability in biological response are important to compare to similar variability in laboratory animals.

Which brings the Dodger to a study of an old favorite chemical, parathion, an organophosphate pesticide. Parathion [ethyl parathion] and methyl parathion, its less toxic to mammals cousin, interest because of competing intoxication and detoxification pathways. For each, the parent compound is oxidized to the corresponding paraoxon, the cholinesterase inhibitor. Parent compound and oxon may be dealkylated. Paraoxonase hydrolyzes and detoxifies the oxon. Concentration of oxon is determined by equilibrium of intoxication and detoxification; biological effect is fraction of cholinesterase inhibition.

Anyway, that brings us to paraoxonase variability. Apparently fancy new techniques have identified 4 forms of paraoxonase, which has biological activity beyond OP detoxification [take that intelligent design advocates]. This study found 5-fold variation of activity toward one substrate, and 20-fold variation toward paraoxon.

Human paraoxonase (PON1) plays a role in detoxification of organophosphorus (OP) compounds by hydrolyzing the bioactive oxons... Some PON1 polymorphisms have been found to be responsible for variations in catalytic activity and expression and have been associated with susceptibility to OP poisoning and vascular diseases. ... The studied population consisted of unrelated individuals (n = 214)... We found a wide interindividual variability of PON1 activity with a unimodal distribution; the range of enzymatic activity toward phenylacetate was 84.72 to 422.0 U/mL, and 88.37 to 1645.6 U/L toward paraoxon.

Toxicology and Applied Pharmacology Volume 205, Issue 3 , 15 June 2005, Pages 282-289

Genetic polymorphisms and activity of PON1 in a Mexican population

A.E. Rojas-Garcíaa, M.J. Solís-Herediaa, B. Piña-Guzmána, L. Vegaa, L. López-Carrillob and B. Quintanilla-Vegaa, ,

aSección Externa de Toxicología, CINVESTAV-IPN, PO Box 14-740, Mexico City, 07300, MexicobInstituto Nacional de Salud Pública, Ave. Universidad No. 655, Col. Santa Ma. Ahuacatitlán, Cuernavaca, Mor., 62508, Mexico Received 18 August 2004; accepted 22 October 2004. Available online 8 December 2004.

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