Effects of malathion on the vascular function in human skin

This work examines the effects of a single low-dose of malathion on the cutaneous vasculature in healthy human skin in vivo. The percutaneous delivery of malathion to the tissue space was established using dermal microdialysis. Scanning laser Doppler imaging was used to assess changes in skin blood flow following exposure to a single low-dose of malathion. The effects of changes in local blood flow on the distribution of malathion within the tissue space were also investigated. In addition the mechanisms by which malathion exerts its effects on the vasculature were investigated both directly by the assay of ACh and nitric oxide in dermal dialysates and indirectly using the response to exogenous ACh as a measure of AChE activity. The role of cutaneous muscarinic receptors in the malathion-induced changes in vascular perfusion was also addressed in this study using dermal iontophoresis to deliver agonists and/or antagonists in the skin and laser Doppler fluximetry to monitor the responses of the vasculature to these agents.The results from the present study demonstrate that malathion is absorbed through the skin and can have direct vasodilator effects which are mediated in part by the increase in tissue levels of ACh and subsequent stimulation of cutaneous muscarinic receptors. This study also showed that tissue levels of malathion are dependent upon local skin blood flow and thus malathion through its effects on the vasculature can influence its own systemic distribution. In addition the results in this study confirm that the responses to ACh are only in part modulated by nitric oxide and demonstrate that at high concentrations ACh has neurogenic effects manifest as flare and itch.Together these findings result in a better understanding of the factors that contribute to the systemic distribution of malathion following its topical application to the skin, as well as of the mechanisms by which OP's modulate the physiological responses of the cutaneous vasculature. The latter provides valuable information about the potential toxic effects following acute exposure to low-doses of OP's.</p

Effects of malathion on the vascular function in human skin

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Modulation of microvascular function following low-dose exposure to the organophosphorous compound malathion in human skin in vivo

This study investigates whether malathion, a widely used organophosphate insecticide, has its effects on cutaneous vasculature in healthy human volunteers through its anticholinergic activity or through the modulation of other, noncholinergic pathways. Acute, low-dose exposure to malathion (10 mg/ml for 5 h under occlusive dressing) caused a significant increase in cutaneous blood flux, monitored by using laser-Doppler flowmetry and imaging. It had little effect on tissue levels of ACh, nitric oxide, and histamine assayed in dermal dialysate collected from malathion-exposed and control-treated skin. The duration of the cutaneous vascular response to exogenous ACh (2%) delivered by iontophoresis was significantly enhanced by preexposure to malathion, both &lt;1 h after its removal and 24 h later (P &lt; 0.001). At &lt;1 h, the time to 50% decay of the response was 24 ± 4 and 50 ± 8 min in control and malathion-treated skin, respectively. Malathion also enhanced the size and duration of the axon reflex-mediated vasoresponse to ACh. The increase in blood flux to malathion and the endothelium-mediated response to exogenous ACh, both in the presence and absence of malathion, were attenuated by pretreatment of the skin with atropine and local anesthesia (P &lt; 0.01). We conclude that short-term exposure to a single low dose of malathion causes prolonged modulation of the physiological function of the cutaneous vasculature and that this is, in part, through its action on acetylcholinesterase at both neuronal and nonneuronal sites

Recovery of nitric oxide from acetylcholine-mediated vasodilatation in human skin in vivo

Objectives: To investigate the relative contribution of nitric oxide (NO) to the vascular and neural mechanisms underlying the ACh-induced vasodilatation in human skin.Methods: ACh was delivered to the skin of the forearm of 28 healthy volunteers using intradermal microdialysis. Subsequent changes in tissue levels of NO and histamine were measured in the dialysate outflow and the associated changes in skin blood flux followed with the use of scanning laser Doppler imaging.Results: ACh caused a dose-dependent increase in skin blood flux measured directly above the probe, associated with a twofold increase in dialysate NO. L-NAME (5 mM) delivered simultaneously via the dialysis probe totally blocked the increase in dialysate NO but only partially attenuated (~30%) the ACh-induced increase in blood flux. At concentrations ≥6.25 mM, ACh also induced a widespread flare response, up to 40 mm in width, accompanied by the sensation of itch. The flare was not blocked by L-NAME or the H1 receptor antagonist levocetirizine, but was reduced by C-fiber blockade. Dialysate histamine levels remained unchanged at all times.Conclusions: These experiments offer further insight into the use of dialysis as an experimental technique in the skin. They provide direct evidence that the skin microvascular response to ACh is only partially mediated by NO. Further they suggest that ACh at higher concentrations can induce an axon-reflex-mediated response that is independent of NO release at the site of dermal provocation or of local histamine release

Effects of local blood flow on the percutaneous absorption of the organophosphorus compound malathion: a microdialysis study in man

Malathion [O,O-dimethyl-S-(1,2-dicarbethoxyethyl)phosphorodithioate] is an organophosphorus insecticide widely used in veterinary medicine and in humans for the treatment of lice. In this study, the rate of the percutaneous absorption of malathion has been measured in human skin, in vivo, using microdialysis. Malathion was detected in tissue dialysate within 30 min of its topical application to the skin of the volar surface of the forearm of healthy volunteers. The concentration of malathion in dialysate increased with lengthening duration of exposure to reach a steady state concentration at 2 h. Prolonged exposure to malathion caused a marked and long-lasting erythema localized to the area of contact. There was no evidence of local tissue oedema or of a neurogenically mediated flare or itch response following topical application. Reducing skin blood flow by the addition of the vasoconstrictor noradrenaline to the dialysis probe perfusate caused an eight-fold increase in the recovery of malathion in the dialysate, which failed to reach a steady state within 5 h. Together, these data confirm that malathion can be absorbed percutaneously and that its distribution within the cutaneous tissue space is influenced by local skin blood flow. They suggest that the increase in skin blood flow caused by malathion may itself play a significant role in enhancing its systemic uptake