toxicological profile for malathion - Agency for Toxic Substances and ...

MALATHION 68
3. HEALTH EFFECTS
Hepatic Effects. No specific reports were located of hepatotoxicity in humans following oral
exposure to malathion. Several studies provide information on hepatic effects in animals following oral
exposure to malathion. A single high-dose of 1,950 mg/kg malathion (95% pure) administered by gavage
to male Wistar rats caused liver congestion and hemorrhage 2 days after dosing (Piramanayagam et al.
1996). Microscopic examination revealed vacuolation of the hepatocytes, necrosis, portal mononuclear
cell infiltration, and microgranuloma formation up to the second day after treatment; these changes
appeared to reverse in subsequent days. Rats treated by gavage with 130 mg malathion/kg/day
(unspecified purity) for 1–2 weeks showed diffuse hydropic degeneration of the liver and those treated
with 390 mg/kg/day had focal necrosis, vacuolar degeneration in the portal hepatocytes, Kupffer cell
hyperplasia and microgranuloma (Piramanayagam and Manohar 2002); without providing details, the
authors indicated that these changes persisted after a recovery period of 7 weeks. A considerable lower
dose of approximately 0.15 mg/kg/day (only dose level tested) of malathion (99% pure) administered in
the drinking water to female Sprague-Dawley rats for 6 months caused hepatocyte degeneration (Lox and
Davis 1983). This finding is puzzling since no significant nonneoplastic alterations have been reported in
the livers of rats and mice administered much higher doses for prolonged periods of time. For example,
NCI (1978) reported no liver alterations in Osborne-Mendel rats administered approximately
622 mg/kg/day malathion (95% pure) in the diet for 80 weeks, but female Fischer-344 rats given
approximately 166 mg/kg/day for 103 showed fatty metamorphosis of the liver, but no degeneration.
B6C3F1 mice treated with up to 2,980 mg/kg/day malathion for 80 weeks had no significant liver effects
(NCI 1978), but a similar study in the same mice strain found hepatocellular hyperplasia at
1,476 mg/kg/day malathion and no significant effect at 167 mg/kg/day (Slauter 1994).
Other studies have monitored liver or serum enzymes commonly used as biomarkers of liver damage. A
dose of 500 mg/kg/day malathion (98% pure) for 3 days induced a decrease in glutathione content and
increased lipid peroxide in the liver of Sprague-Dawley rats (Prabhakaran and Devi 1993; Prabhakaran et
al. 1993). A single gavage dose of 500 mg/kg malathion (96% pure) or intermittent gavage doses of
500 mg/kg/day for 4 weeks increased serum alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) activities, also in rats (Enan 1983). A NOAEL of 50 mg/kg (following either
single dose or 21-day dosing) for serum transaminase activities in rats was reported by Abdel-Rahman et
al. (1985). A dose of 137.5 mg/kg/day for 32 days significantly increased AST, ALT, and alkaline
phosphatase (AP) activities in the liver (Husain et al. 1987). A dose of 25 mg/kg/day malathion
(unspecified purity) administered by gavage for 7 days to female Sprague-Dawley rats had no significant
effect on the activities of liver microsomal enzymes (Lechner and Abdel-Rahman 1985). Data on hepatic
effects in mice following acute exposure of malathion are limited to a report of increased glutathione