Amplified interactive toxicity of chemicals at nontoxic levels: Mechanistic considerations and implications to public health

Journal Article · Tue Nov 01 04:00:00 EST 1994 · Environmental Health Perspectives

DOI:https://doi.org/10.1289/ehp.94102s9139· OSTI ID:494143

Mehendale, H M ^[1]

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1. Northeast Louisiana Univ., Monroe, LA (United States)

It is widely recognized that exposure to combinations or mixtures of chemicals may result in highly exaggerated toxicity even though the individual chemicals might not be toxic. Assessment of risk from exposure to combinations of chemicals requires the knowledge of the underlying mechanism(s). Dietary exposure to a nontoxic dose of chlordecone (CD; 10 ppm, 15 days) results in a 67-fold increase in lethality of an ordinarily inconsequential dose of CCl{sub 4} (100 {mu}l/kg, ip). Toxicity of closely related CHCl{sub 3} and BrCCl{sub 3} is also enhanced. Phenobarbital (PB, 225 ppm, 15 days) and mirex (10 ppm, 15 days) do not share the propensity of CD in this regard. Exposure to PB + CCl{sub 4} results in enhanced liver injury similar to that observed with CD, but the animals recover and survive in contrast to the greatly amplified lethality of CD + CCl{sub 4}. Investigations have revealed that neither enhanced bioactivation of CCl{sub 4} nor increased lipid peroxidation offers a satisfactory explanation of these findings. Additional studies indicate that exposure to a low dose of CCl{sub 4} (100 {mu}l/kg, ip) results in limited jury, which is accompanied by a biphasic response of hepatocellular regeneration (6 and 36 hr) and tissue repair, which enables the animals to recover from injury. Exposure to CD + CCl{sub 4} results in suppressed tissue repair owing to an energy deficit in hepatocytes as a consequence of excessive intracellular influx of Ca{sup 2+} leading initially to a precipitous decline in glycogen and ultimately to hypoglycemia. Supplementation of cellular energy results in restoration of the tissue repair and complete recovery from the toxicity of CD + CCl{sub 4} combination. In contrast, only the early-phase hepatic tissue repair (6 hr) is affected in PB + CCl{sub 4} treatment, but this is compensated for by a greater stimulation of tissue repair at 24 and 48 hr resulting in recovery from liver and animal survival. 85 refs., 7 figs., 7 tabs.

• Sponsoring Organization: USDOE
• OSTI ID: 494143
• Report Number(s): CONF-9207255--; CNN: Grant AFOSR-88-0009
• Journal Information: Environmental Health Perspectives, Journal Name: Environmental Health Perspectives Journal Issue: Suppl.9 Vol. 102; ISSN EVHPAZ; ISSN 0091-6765
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
56 BIOLOGY AND MEDICINE
APPLIED STUDIES
ANIMALS
BENZENE
CARBON TETRACHLORIDE
CHLOROFORM
MIXTURES
OCCUPATIONAL EXPOSURE
PHENOBARBITAL
PUBLIC HEALTH
RISK ASSESSMENT
TOXICITY