Graduate Thesis Or Dissertation
 

The effects of increased body burdens of lead on lindane and dieldrin toxicity

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  • The entire human population is chronically exposed to various contaminants, including lead and chlorinated hydrocarbon pesticides. Studies were undertaken to assess the effects of chronic exposure to lead on the toxicities of two such pesticides, lindane and dieldrin. Mice were given lead as the acetate in drinking water, at levels of 75, 150 or 300 ppm lead for eight weeks. The acute LD50 of lindane (98 mg/kg) given in corn oil by oral intubation was not altered significantly (P > .05) by administration of 150 ppm lead. Similarly, the acute LD50 of dieldrin (45 mg/kg), given in corn oil by oral intubation, was not changed significantly (P > .05) by the same lead exposure. In subacute studies, lindane was given daily by oral intubatiop in corn oil at a level of 40 mg/kg for the final two weeks of lead exposure. The excretion of delta-aminolevulinic acid in the urine was increased in a dose-related fashion by lead but was unaffected by lindane. There was no evidence of significant interaction between the two agents. Urinary coproporphyrin excretion was increased slightly by both agents, and when lindane was given to mice receiving 300 ppm lead, levels rose from a control urinary concentration of 0.21 microgram per ml to 0.37 microgram per ml (P < .05). Urinary excretion of uroporphyrin was not altered by either agent. Thus, lead and lindane apparently interacted in an additive fashion at at least one step in the heme synthesis pathway, and failed to interact at at least two steps. Lead depressed blood hemoglobin concentration (from a control value of 13.5 grams per 100 ml to 12.8 grams per 100 ml), an effect predictable from the blockade of heme biosynthesis by the metal. Lindane did not affect hemoglobin concentration when given by itself but prevented the fall in concentration elicited by lead. Hematocrit was decreased in a dose-related fashion (from 43.7% to 41.1%) by lead, and lindane appeared to accentuate the decrease (40.0% when both were given). The agents were thus seen to interact at two or more sites, one of which was probably the heme biosynthetic pathway. Levels of hepatic microsomal cytochrome P-450 were depressed in a dose-related fashion upon administration of lead. In mice receiving 300 ppm lead, levels were depressed to about 50% of the control level. This effect suggested the possibility that individuals exposed to lead may suffer impairment of oxidative metabolic pathways dependent upon cytochrome P-450. This could have the effect of increasing the toxicity of a compound taken into the body, or of increasing the duration of the action of the compound. Lindane increased levels of cytochrome P-450 an average of 83% over respective counterparts not receiving lindane. This effect was probably related to an induction of hepatic microsomal enzyme systems. Lindane, at the level given, overcame the effects of lead on cytochrome P-450 levels. Despite the effect of lead on cytochrome P-450, lead administration did not affect the length of time mice slept (P > .05) when given 40 mg/kg pentobarbital sodium. Lindane reduced sleep time from 16.4 minutes to 8.5 minutes (P < .05) whether or not lead was given. This effect was attributed to induction of hepatic microsomal pentobarbital-metabolizing enzymes. Lead did not alter susceptibility to clonic seizures as determined by intravenous infusion of pentylenetetrazol at a constant rate. Lindane, however, increased by an average of 53% the amount of pentylenetetrazol necessary to induce seizures; when seizures occurred in lindane-treated mice they were often fatal in outcome, whereas mice not given lindane rarely died from this procedure. Lead appeared to raise mortality levels in this test. Dieldrin decreased seizure threshold an average of 31%. It was concluded that lindane and dieldrin elicit central stimulation by different mechanisms. When seizure susceptibility was determined by the low-frequency electroshock test, lead appeared to increase susceptibility slightly, whereas lindane consistently decreased it to a significant extent (an average decrease of 23%) and dieldrin raised susceptibility (an average increase of 26%). The length of time mice were able to maintain equilibrium on a rotating horizontally-oriented wooden rod was determined. Lead administration did not affect this parameter even when given in concentrations up to 4800 ppm for three months. Four weeks' administration of 0.5 or 1.0 ppm dieldrin in food impaired the ability of mice to remain on the rod. When lead administration was added to dieldrin feeding, the agents appeared to act antagonistically in this test. Thus, it appeared that this test is valid for assessing chronic dieldrin intoxication in mice, but that lead administration renders the results obtained from the test inconclusive. It was concluded that the mouse is a useful laboratory animal in studies of the biochemical and hematologic effects of chronic lead poisoning, but is not useful in the assessment of central damage due to lead. If the findings of these studies can be extrapolated to humans, it may be concluded that although the lethality of lindane is unaffected by chronic administration of lead, an individual exposed to both agents suffers additive effects, such as was seen in the coproporphyrin study. Therefore, an individual exposed to lead should take special precaution to avoid exposure to lindane, and an individual exposed to lindane should guard against exposure to lead.
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