Lead toxicity neurotoxicity

Neurotoxicity. There is a very large database on the neurotoxic effects of lead. The most severe neurobehavioral effect of lead toxicity in adults is lead encephalopathy (Kehoe 1961a Kumar et al. 1987 Smith et al. 1978). Early symptoms, which may develop within weeks of initial exposure, include dullness, irritability, poor attention span, headache, muscular tremor, loss of memory, and hallucinations. These symptoms worsen, sometimes abruptly, to delirium, convulsions, paralysis, coma, and death. 

When exposed to mixtures, chemicals in the exposure medium may affect each other s uptake by humans in a manner that is analogous to some of the bioavailability effects outlined here for environmental species. This was, for instance, shown for the neurotoxicity of EPN (O-ethyl-O-4-nitrophenyl phenylphosphono-thionate), which was enhanced by aliphatic hydrocarbons due in part to increased dermal absorption (Abou-Donia et al. 1985). It was also shown that dietary zinc inhibits some aspects of lead toxicity, which could in part be explained by decreasing dietary lead absorption (Cerklewski and Forbes 1976). Other examples of interactions of chemicals at the uptake phase in humans, which may in part be related to bioavailability interactions, are summarized in Table 1.3. 

The most important risk factors for acyclovir nephrotoxicity are intravascular volume contraction, preexisting kidney desease, and the use of a high-dose, rapid bolus intravenous infusion [7] Nephrotoxicity with oral acyclovir has been reported only rarely [23] The main non-renal toxicities of acyclovir are gastrointestinal and neurologic side effects, which primarily occur in patients on high-dose intravenous acyclovir. As acyclovir is primarily cleared by the kidney, lower intravenous doses and even oral administration can lead to neurotoxicity in patients with decreased kidney function from either CKD or AKI [15,17, 24, 25]. 

Hexachlorobenzene Lead Mercury Probable carcinogen Blood system toxic, neurotoxicity Neurotoxic... 

Lead Blood system toxic, neurotoxicity Auto exhaust, fuel additive 7-30 days removed by deposition 270-820 ng m - —... 

Standard Phase I entry criteria were used in GCP controlled trials, although patients known to have hrain metastases were excluded due to concern that brain vascular permeability might lead to neurotoxicity. Appreciating that conjugate pharmacokinetics could lead to unexpected anthracycline toxicities. 

Sachs, 1974) indicated that the incidence of high lead exposure appeared to be falling. This was due to such factors as the changes in the population of the children being screened, increased awareness about lead neurotoxicity, and slum clearance programmes. Death from lead poisoning is now almost zero and encephalopathy is rare. This in turn has focussed attention on the subclinical effects of lead toxicity. 

Although it is possible to measure certain neurochemical parameters in humans, the understanding of molecular mechanisms of lead toxicity must depend on animal experimentation. Alterations in neurochemistry may precede other neurotoxic effects and be the basis for the expressions of altered behaviour, pharmacological response or cell pathology. 

Two enzyme systems have shown themselves to be extremely sensitive to lead at low levels. The first of these is D-amino laevulinic acid dehydratase (d-ALAD), the initial and rate limiting step in the porphyrin synthetic pathway. In both experimental (Barlow et al., 1977) and clinical studies (Piomelli et al., 1980) this enzyme is potently inhibited by lead. In a review of dose-dependent low level lead effects, Zielhuis (1975) calculated a no effect level for this enzyme at about 10/tg Pb/lOOml blood in man. Other enzymes in the porphyrin synthetic pathway are also affected by lead, e.g. ferrochelatase, the enzyme responsible for the insertion of haem into the porphyrin precursor protoporphyrin IX (Moore, 1975), but this is probably due to D-ALAD-related interactions. Silbergeld and Lamon (1980) have speculated that the neurotoxic effects of lead may be due in part to a competitive interaction involving amino laevulinic acid at neuronal receptors, as there may be similarities between features of lead toxicity and some of the porphyrinopathic diseases (Moore et al., 1980). 

A complete and detailed work history is important in the initial evaluation. A listing of all previous employment with information on job description, exposure to fumes or dust, known exposures to lead or other toxic substances, a description of any personal protective equipment used, and previous medical surveillance should all be included in the worker s record. Where exposure to lead is suspected, information concerning on-the-job personal hygiene, smoking or eating habits in work areas, laundry procedures, and use of any protective clothing or respiratory protection equipment should be noted. A complete work history is essential in the medical evaluation of a worker with suspected lead toxicity, especially when long term effects such as neurotoxicity and nephrotoxicity are considered. 

Table 22.3 presents the full-spectrum of dose—toxic response relationships for lead toxicity in adults in terms of lowest reported adverse effect level thresholds. As with the earlier tables, only the lowest values for PbB in the associations specific for the indicated range are identified. It is also understood with these adult tabulations that as PbB values rise above lowest levels of determined associations, those toxic effects increase in severity and multiplicity. Toxicity criteria for reliability and validity parallel those enumerated for the earlier childhood tables. A number of dose-responses scaled to dose/exposure are identified in the table. In many cases, including hematotoxicity, peripheral neurotoxicity, and nephrotoxicity, effects are qualitatively similar but occur at higher empirically measured thresholds. 

The ninth through eleventh ways utilize erythrocytic protoporphyrin (EP), and offer several possible advantages. Not only does blood EP integrate lead exposure over a longer time than does blood lead, but EP also provides information about a child s biochemical reaction to a given blood lead dose, which may be idiosyncratic. Also, if EP itself is a toxic intermediary in lead s neurotoxicity, EP values might correlate better with Mental Development Index scores than do lead. 

Phosphonothioate Esters of Phenols. Phosphonates with a single P—C bond are highly toxic and persistent iasecticides but have not been used extensively because some compounds produce delayed neuropathy leading to irreversible paralysis ia higher animals, including humans. Such compounds specifically inhibit an enzyme, neurotoxic esterase, that is responsible for the growth and maintenance of long nerve axons (31,32). 

Starvation or disease can lead to rapid release of the stored xenobiotic and to delayed toxic effects. In one well-documented case in the Netherlands (see Chapter 5), wild female eider ducks (Somateria mollissima) experienced delayed neurotoxicity caused by dieldrin. The ducks had laid down large reserves of depot fat before breeding, and these reserves were run down during the course of egg laying. Dieldrin concentrations quickly rose to lethal levels in the brain. Male eider ducks did not lay down and mobilize body fat in this way and did not show delayed neurotoxicity due to dieldrin. 

Opiate drug exposure has a significant impact on HIV infection as well as progression to HIV-associated dementia. On a cellular level it is comprehendible that drugs of abuse such as opioids would reduce the threshold for neurotoxicity such that a marginally toxic insult would now be exacerbated and lead to cell death or injury... 

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