Toxic nephropathy

The alimentary symptoms may be overshadowed by neuromuscular dysfunction, accompanied by signs of motor weakness that may progress to paralysis of the exterior muscles or the wrist (wrist drop), and less often, of the ankles (foot drop). Encephalopathy, the most serious result of lead poisoning, frequendy occurs in children as a result of pica, ie, ingestion of inorganic lead compounds in paint chips this rarely occurs in adults. Nephropathy has also been associated with chronic lead poisoning (147). The toxic effects of lead may be most pronounced on the developing fetus. Consequendy, women must be particulady cautious of lead exposure (148). The U.S. Center for Disease Control recommends a blood level of less than 10 p.m per 100 mL for children. 

Lead is toxic to the kidney, cardiovascular system, developiag red blood cells, and the nervous system. The toxicity of lead to the kidney is manifested by chronic nephropathy and appears to result from long-term, relatively high dose exposure to lead. It appears that the toxicity of lead to the kidney results from effects on the cells lining the proximal tubules. Lead inhibits the metaboHc activation of vitamin D in these cells, and induces the formation of dense lead—protein complexes, causing a progressive destmction of the proximal tubules (13). Lead has been impHcated in causing hypertension as a result of a direct action on vascular smooth muscle as well as the toxic effects on the kidneys (12,13). 

Increased mortality was observed in both male rats (at doses of 20.4 mg/kg/day and above) and male mice (at doses of 0.46 mg/kg/day and above) in a 2-year bioassay conducted by the National Cancer Institute (NCI 1978). The authors attributed the excessive mortality in the male rats to treatment-related toxic nephropathy. The high mortality in male mice was possibly due to fighting since no other treatment-related cause for the deaths could be determined. Survival in females of both species was unaffected by endosulfan (NCI 1978). However, survival was significantly decreased in female rats that consumed 5 mg/kg/day for 2 years (FMC 1959b), and in female mice that consumed approximately 2.9 mg technical endosulfan/kg/day for 2 years (Hack et al. 1995 Hoechst 1988b). In these studies, survival in male rats was not affected at 5 mg/kg/day for 2 years (FMC 1959b) and survival in male mice was not affected at 2.51 mg/kg/day for 2 years (Hoechst 1988b). 

Several studies conducted in children known to have lead toxicity, indicate that nephropathy occurs in children only at PbB >80 pg/dL, and usually exceeding 120 pg/dL (NAS 1972). 

The mechanism of renal toxicity is not clear. Because the spectrum of kidney lesions observed in male rats (Gorzinski et al. 1985 NTP 1989) resembled those for 2p-globulin nephropathy, hexachloroethane-induced kidney lesions may, in part, be due to hexachloroethane binding to this protein. On the other hand, renal toxicity was observed in female rats and did not present the same sequence of lesions. This suggests the effects in males may not be totally due to 2p-globulin. Specific methods to minimize renal toxicity, based on mechanism of action, cannot be proposed at this time. 

Chronic-Duration Exposure and Cancer. No studies were located in humans following chrome-duration exposure to hexachloroethane for any exposure route. No chronic animal studies were conducted using the inhalation route of exposure. In oral studies with rats, the kidney was identified as a primary target organ in males and females (NTP 1989). The kidney damage in male rats was the result of hyaline droplet nephropathy and, accordingly, was not suitable as the basis for an oral MRL. In contrast to acute- and intermediate-duration oral exposure, liver toxicity was not evident in rats following chronic oral exposure. There were no studies of chronic dermal exposure to hexachloroethane. 

Bromoethylamine (11.133, R = Br, Fig. 11.18) is a potent nephrotoxin used to create an experimental model of nephropathy. Its mechanism of toxicity is postulated to involve perturbation of mitochondrial function, and its metabolism was investigated in a search for toxic metabolites. In rat plasma, 2-bromoethylamine was converted to aziridine (11.134), formed by intramolecular nucleophilic substitution and bromide elimination [155], Another major metabolite was oxazolidin-2-one (11.136). This peculiar metabolite resulted from the reaction of 2-bromoethylamine with endogenous carbonate to form carbamic acid 11.135, followed by cyclization-elimination to oxazoli-din-2-one. In aqueous media containing excess carbonate, the formation of... 

Toxic nephropathy of the type seen after inhalation exposure of rats (see Section 2.2.1.2) was not identified in rats or mice in the NCI (1978) gavage bioassay of 1,2-dibromoethane. 

Renal lesions or changes in renal function in humans chronically exposed to 1,2-dibromoethane have not been identified. Following chronic inhalation exposure to 1,2-dibromoethane, rats developed toxic nephropathy (NTP 1982). 

The mechanisms of action for nephrotoxic (with the exception of 2. -globulin-mediated nephropathy specific to male rats) or hematotoxic effects have not been clearly delineated, and with the available information, it is difficult to speculate how 1,4-dichlorobenzene might cause such effects. More information concerning the mechanisms of action for blood and kidney effects are needed before methods for blocking those mechanism and reducing toxic effects can be developed. 

In a follow-up study in mice, exposure to DEA, via drinking water or by topical application, caused dose-dependent toxic effects in the liver (hepatocellular cytological alterations and necrosis), kidney (nephropathy and tubular epithelial necrosis in males), heart (cardiac myoqn e degeneration), and skin (site of application ulceration, inflammation, hyperkeratosis, and acanthosis). Doses ranged from 630 to 10,000 ppm in the drinking water and from 80 to 12 50 mg/kg in the topical application study. 

In chronic studies, DMMP was administered by gavage in corn oil for up to 2 years at doses of 500 or 1000 mg/kg/day to rats and at doses of 1000 or 2000mg/kg/day to mice. " Survival in dosed male rats was reduced, due in part to renal toxicity. Lesions of the kidney included increased severity of spontaneous age-related nephropathy including calcification, hyperplasia of the tubular and transitional epithelium, tubular cell adenocarcinomas, and transitional cell papillomas and carcinomas. Similar lesions were not seen in female rats or in mice of either sex, although reduced survival in male mice prevented adequate analysis. The... 

Gavage administration of 0.62 or 1.24 mmol/%/day to rats for 21 days did not cause clinical signs of toxicity or microscopic effects in either the liver or kidney. The inability to produce hyalin droplet nephropathy suggests that kidney neoplasms would not occur in rats in 2-year studies. ... 

Bernard A, Lauwerys RR. 1991. Proteinuria changes and mechanisms in toxic nephropathies. Toxiocology 21 373-405. 

Sunderman FW Jr, Horak E. 1981. Biochemical indices of nephrotoxicity, exemplified by studies of nickel nephropathy. In Brown SS, Davies DS, eds. Organ-directed toxicity Chemical indices and mechanisms. London, UK Peigamon Press, 52-64. 

Nephritis. Inflammation of the kidney. Nephropathy. Disease of the kidneys. Nephrotoxic. Toxic or destructive to kidney cells. 

Lead Inorganic lead oxides and salts Gastrointestinal, respiratory Soft tissues redistributed to skeleton (> 90% of adult body burden) CNS deficits peripheral neuropathy anemia nephropathy hypertension reproductive toxicity Inhibits enzymes interferes with essential cations alters membrane structure Renal (major) feces and breast milk (minor)... 

Iodinated radiographic contrast media can cause acute renal insufficiency, perhaps as a result of reduced renal blood flow, an intrarenal osmotic effect, or direct tubular toxicity (58). Diuretics, calcium channel blockers, adenosine receptor antagonists, acetylcysteine, low-dose dopamine, the dopamine Di receptor agonist fenoldopam, endothelin receptor antagonists, and captopril have all been used to prevent contrast nephropathy. 

Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have occasionally been reported. Intravenous infusion may be associated with reversible renal dysfunction due to crystalline nephropathy or neurologic toxicity (eg, tremors, delirium, seizures) however, these are uncommon with adequate hydration and avoidance of rapid infusion rates. Chronic daily suppressive use of acyclovir for more than 10 years has not been associated with untoward effects. High doses of acyclovir cause testicular atrophy in rats, but there has been no evidence of teratogenicity to date in a cumulative registry and no effect on sperm production was demonstrated in a placebo-controlled trial of patients receiving daily chronic acyclovir. 

I Heyman SN, Rosen S, Brezis M. Radiocontrast nephropathy a paradigm for the synergism between toxic and hypoxic insults in the kidney. Exp Nephrol 1994 2 153-157. 

Mutti A, Lucertini S, Valcavi P, et al. 1985 a. Urinary excretion of brush-border antigen revealed by monoclonal antibody Early indicator of toxic nephropathy. Lancet ii 914-917. 

Van Vleet, T. R., and Schnellmann, R. G. Toxic nephropathy Environmental chemicals. Semin. Nephrol. 23, 500-508, 2003. 

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