Alkyldiol antidotes to ethylene glycol toxicity in mice.

A series of alkyldiols were compared to ethanol or pyrazole as antidotes in ethylene glycol toxicity. Mouse liver alcohol dehydrogenase oxidized ethanol and a series of alkyldiols. The K_m values in millimoles per liter determined from the assays were 0.4 with ethanol, 53 with ethylene glycol, 14 with propylene glycol, 5.4 with 1,3-propanediol, 3.8 with 1,2-butanediol, 1.5 with 1,3-butanediol, 0.5 with 1,4-butanediol, 56 with 2,3-butanediol, 0.23 with 1,5-pentanediol, and 0.031 with 1,6-hexanediol. These data indicated that ethanol and the alkyldiols, with the exception of 2,3-butanediol, had higher affinities for mouse liver alcohol dehydrogenase than ethylene glycol. Propylene glycol (27.2 mmol/kg), 1,2-butanediol (11.2 mmol/kg), and 1,3-butanediol (22.3 mmol/kg) were the only alkyldiols found to protect mice. Acute and delayed toxicity and hexobarbital sleeping time studies indicated that the alkyldiols which protected the mice were, in general, the least toxic and least hypnotic of the alkyldiols. Therapeutic ratios found by dividing the 144 hr LD50 of an antidote by the dose which produced the maximum antidotal effect were 3.17 for ethanol, 2.56 for pyrazole, 6.16 for propylene glycol, 4.15 for 1.2-butanediol, and 5.11 for 1,3-butanediol. These data suggest that the alkyldiol antidotes are effective and may be safter than either ethanol or pyrazole.     

Embryotoxic effects of ethylene glycol monomethyl ether in mice

An embryotoxicity study on ethylene glycol monomethyl ether (EGM) was carried out in ICR mice. They were given EGM daily at 6 dose levels (31.25, 62.5, 125, 250, 500 or 1000 mg/kg body wt) by gastric intubation on days 7 through 14 gestation. On day 18 of gestation all fetuses were examined. Marked and dose-related embryotoxic effects were observed. Skeletal and gross anomalies, reduced fetal weight and feral death were all observed at lower dosages of EGM, while marked leucopenia of the dams occured at the highest dose.     

Repeated inhalation toxicity of diphenyl oxide in experimental animals.

Repeated inhalation studies using rats, rabbits, and dogs were conducted at mean exposure concentrations of 0, 4.9, and 10.0 ppm diphenyl oxide (DPO) vapor. Exposures were 7 hr per day, 5 days per week for a total of 20 exposures. Additional groups of rats were exposed 7 hr per day to 0 or 20 ppm DPO vapor for a total of 20 exposures. No signs of toxicity or irritation were observed in animals exposed to 4.9 ppm. Eye and nasal irritation were observed in rats and rabbits but not dogs exposed to 10.0 ppm and in rats exposed to 20 ppm. Aside from this irritation no other signs of toxicity were discerned.     

Benzene inhalation produces leukemia in mice

Female C57Bl/6 mice were exposed to 300 ppm benzene 6 hr/day, 5 days/week for 16 weeks and then held for lifetime observation. Sixty-four weeks after commencement of the study, 10 of 90 exposed mice had died as opposed to only 1 of 88 controls. Of the 10 exposed mice that died, 6 had thymic lymphomas, 2 had unspecified lymphomas, 1 was killed when moribund and found leukemia-free, and 1 was undiagnosed due to autolysis and partial cannibalization. The single dead control animal did not have lymphoma or leukemia. These data provide proof of the leukemogenicity of benzene in female C57Bl/6 mice.     

The role of cytochrome P-450 in the toxicity of fluroxene (2,2,2-trifluoroethyl vinyl ether) anaesthesia in vivo.

Induction of type P-450 cytochromes in rats by i.p. injections of phenobarbital potentiated the toxicity (100% mortality) of the normally non-toxic anaesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether). The toxic effects were eliminated by administration of 2-allyl-2-isopropylacetamide prior to anaesthesia. Hepatic microsomal cytochrome P-450 levels of the dead rats were markedly diminished relative to unanaesthetised induced controls. Induction by 3-methylcholanthrene and 3,4-benzpyrene did not potentiate toxic effects of fluroxene but anaesthesia after mixed induction with 3-methylcho-lanthrene and phenobarbital manifested toxicity more rapidly than induction with phenobarbital alone. When 2,2,2-trifluoroethyl ethyl ether was used as the anaesthetic similar toxic effects were observed except that levels of type P-450 cytochromes were not depressed at the time of death and induction with 3-methylcholanthrene did potentiate toxic effects with this anaesthetic. We interpret these results to indicate that cytochrome P-450 catalyses an essential step in the production of toxic metabolites from fluroxene and that elevated concentrations of the enzyme are required to potentiate the toxicity. Apparently, cytochrome P-448 does not metabolize fluroxene and elevated levels of this enzyme therefore do not potentiate the toxicity of fluroxene anaesthesia. The ability of fluroxene to destroy cytochrome P-450 resides in its vinyl group while the toxic metabolite arises from the trifluoroethyl moiety.     

Ethylene glycol monobutyl ether: Acute, 9-day,and 90-day vapor inhalation studies in Fischer 344 rats

The acute 4-hr LC50 (with 95% confidence limits) for Fischer 344 rats was determined to be 486 (339 to 696) ppm of ethylene glycol monobutyl ether (EGBE) for males and 450 (315 to 645) ppm for females. Notable observations included loss of coordination, red stained urine, and enlarged discolored kidneys at 867 and 523 ppm. In a subsequent study, rats were exposed for 9 days (6 hr/day) to EGBE concentrations of 245, 86, 20, or 0 (control) ppm. There were significant depressions of red blood cell (RBC) count (approximately 20% below control values), hemoglobin (Hgb), and mean corpuscular hemoglobin (MCH) concentration and increases in nucleated erythrocytes, reticulocytes, and lymphocytes in males and females of the 245 ppm group. Decreased body weight gains and increased liver weights were also found. A 14-day postexposure recovery showed substantial reversal of the affected blood parameters. Similar, but less marked, hematologic effects were observed in rats exposed to 86 ppm of EGBE, while rats of the 20 ppm group were indistinguishable from controls. In a 90-day study, rats were exposed to EGBE concentrations of 77, 25, 5, or 0 ppm for 13 weeks (6 hr/day, 5 days/week). Slight, but statistically significant, decreases in RBC (13% below control) and Hgb, accompanied by an increase in MCH (11% above control) were observed in the 77 ppm-exposed females after 6 weeks. At the conclusion of the 90-day exposure regimen, the hematologic effects seen in the females had lessened (RBC was 7% below control) or returned to control value ranges. Furthermore, no treatment-related differences were found in body weight, organ weights, urine or serum chemistries, gross lesions, or microscopic lesions in males or females. There were no significant biological effects in rats exposed subchronically to 25 or 5 ppm. The subtle hematologic findings of these studies confirm the known RBC perturbations of EGBE.     

The role of isocyanates in the toxicity of antitumour haloalkylnitrosoureas

The cytotoxicity of the antitumour nitrosoureas BCNU and CCNU and the isocyanates which they liberate (chloroethylisocyanate and cyclohexylisocyanate respectively) has been measured utilising an in vitro-in vivo bioassay. Lines of the TLX5 lymphoma and L1210 leukaemia were used which were either sensitive or resistant to nitrosoureas in vivo. An estimated logarithmic cell kill produced by each compound in vitro (before injecting the cells into animals) was calculated by reference to assays of the survival time of animals given from 2 × 10⁵ to 2 × 10⁰ cells of each line. Resistance to both BCNU and CCNU was observed in vitro in the cell lines of the TLX5 lymphoma made resistant to either BCNU or a dimethyltriazene in vivo. The latter tumour was cross-resistant in vivo to nitrosoureas. Resistance in vitro to nitrosoureas was also observed in a line of L1210 leukaemia which had had resistance to BCNU induced in vivo. The nitrosourea resistant TLX5 lymphomas were cross-resistant in vitro to both cyclohexylisocyanate and chloroethylisocyanate whereas the nitrosourea resistant L1210 line showed no cross-resistance to cyclohexylisocyanate and marginal cross-resistance to chloroethylisocyanate. The results suggest that the TLX5 lymphoma, which is naturally resistant to alkylating agents of the 2-chloroethylamine type, may be sensitive in vivo to nitrosoureas as a consequence of the intracellular release of isocyanates. This hypothesis was supported by the finding that the resistant TLX5 lymphoma showed no cross-resistance to other electrophilic agents, for example formaldehyde, monomethyltriazene or HN2. The transport of nitrosoureas into the sensitive and resistant cell lines was similar in profile and there was no difference in the concentration of non-protein thiols.     

Nature of the toxicity of cyclosporin A in the rat

The potent immunosuppressive agent Cyclosporin A (CyA) causes a spectrum of toxicological effects in rats, of which the most striking is weight loss. Pair-feeding experiments have shown that this is caused, in part, by a short period of anorexia. However, even when the food intake has become normal the rats receiving CyA fail to gain weight. That CyA at the doses used causes increased protein catabolism is also indicated by a fall in serum albumin and a marked rise in blood urea unaccompanied by a corresponding rise in creatinine. CyA is mildly and reversibly hepatotoxic and there is slight nephrotoxicity in the rat on the basis of histology and small elevations in creatinine.     

Potentiation of duodenal ulcerogenic action of acrylonitrile by PCB or phenobarbital in the rat

Pretreatment of rats with the polychlorinated biphenyl (PCB) Aroclor 1254 or phenobarbital markedly increased the duodenal ulcerogenic action of acrylonitrile. The extent of forestomach and hepatic lesions in these rats, on the other hand, was not modified. The duodenal ulcers produced by Aroclor 1254 and acrylonitrile morphologically resembled the ulcers induced in other animal models of the human duodenal ulcer disease. The possible mechanisms of this potentiation of acrylonitrile action are discussed.     

Effect of papain on bee venom toxicity

The use of Adolph's Meat Tenderizer, which contains the enzyme papain, has been recommended for the treatment of bee stings, although no controlled animal or clinical data existed to support this treatment. Using mice as the test animals, we could find no evidence for antagonism of bee venom lethality or intradermal lesions by papain or Adolph's Meat Tenderizer administered following the venom. It therefore can be tentatively concluded that no positive effect would be expected by the application of these preparations in the usual clinical situation. Inactivation of bee venom only occurred when the venom and papain were mixed together prior to injection. In contrast, hydrocortisone ointment 0.5% was highly effective in decreasing the size of lesions produced by the prior intradermal injection of bee venom.     

The synergism of n-hexane-induced neurotoxicity by methyl isobutyl ketone following subchronic (90 days) inhalation in hens: induction of hepatic microsomal cytochrome P-450

The effect of methyl isobutyl ketone (MiBK) on n-hexane-induced neurotoxicity was investigated via inhalation in seven groups of five hens each for 90 days followed by a 30-day observation period. One group was exposed to vapors containing 1000 ppm n-hexane and another group to vapors having 1000 ppm MiBK. Four groups were exposed simultaneously to 1000 ppm of n-hexane and 100, 250, 500, or 1000 ppm MiBK. Another group was exposed similarly to ambient air in an exposure chamber and used as a control. Hens continuously exposed to 1000 ppm MiBK developed leg weakness with subsequent recovery, while inhalation of the same concentration of n-hexane produced mild ataxia. Hens exposed to mixtures of n-hexane and MiBK developed clinical signs of neurotoxicity, the severity of which depended on the MiBK concentration. Thus, all hens exposed to 1000 ppm n-hexane in combination with 250, 500, or 1000 ppm MiBK progressed to paralysis. Hens continuously exposed to 1000/100 n-hexane/MiBK showed severe ataxia which did not change during the observation period. The neurologic dysfunction in hens exposed simultaneously to n-hexane and MiBK was accompanied by large swollen axons and degeneration of the axon and myelin of the spinal cord and peripheral nerves. The results indicate that the nonneurotoxic chemical MiBK synergized the neurotoxic action of the weak neurotoxicant n-hexane since the coneurotoxicity coefficient for joint exposure was more than two times the additive effect of each treatment alone. In another experiment, to investigate the mechanism of MiBK synergism of n-hexane neurotoxicity, continuous inhalation for 50 days of 1000 ppm n-hexane had no effect on hen hepatic microsomal enzymes, whereas inhalation of 1000 ppm MiBK for 50 days or a mixture of 1000 ppm of each of n-hexane and MiBK for 30 days significantly induced aniline hydroxylase activity and cytochrome P-450 contents in hen liver microsomes. Liver microsomal proteins from these hens and from hens treated with beta-naphthoflavone (beta-NF) and phenobarbital (PB) were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. While beta-NF increased the 55-kDa band (1408%), PB, MiBK, and MiBK/n-hexane increased the protein band (49 kDa) (258, 335, and 253%, respectively), indicating that MiBK induces chicken hepatic cytochrome P-450. The results suggest that the synergistic action of MiBK on n-hexane neurotoxicity may be related to its ability to induce liver microsomal cytochrome P-450, resulting in increased metabolic activation of n-hexane to more potent neurotoxic metabolites.     

Fluroxene (2,2,2-trifluoroethyl vinyl ether) mediated destruction of cytochrome P-450 in vitro.

Incubation of rat hepatic microsomes with an NADPH generating system and the anaesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether) at 30° resulted in the destruction of hepatic cytochrome P-450 in excess of that observed in the presence of the NADPH generating system alone. The extent of destruction of cytochrome P-450 was markedly enhanced by pre-induction of cytochrome P-450 with phenobarbital. Induction with 3-methylcholanthrene or 3,4-benzpyrene, which induce cytochrome P-448, enhanced the overall level of cytochrome destruction. No destruction was observed when CO was added to the system prior to the addition of the anaesthetic, or when NADH replaced NADPH or when fluroxene was replaced by its chemically reduced from, 2,2,2-trifluoroethyl ethyl ether. The fluorexene potentiated destruction of cytochrome P-450 was accompanied by the loss of heme from the microsomes but not by the appearance of cytochrome P-420 nor by the loss of cytochrome b₅ or NADPH-cytochrome c reductase. We conclude that cytochrome P-450 is specifically destroyed by fluroxene in a metabolic process involving destruction of its heme group. The vinyl group of the anaesthetic is essential for the destructive process.     

Effect of phenobarbital on cephaloridine toxicity and accumulation in rabbit and rat kidneys

Cephaloridine causes necrosis of renal proximal tubules in humans and laboratory animals. This antibiotic nephrotoxicity in rats has been shown to be reduced by mixed-function oxidase (MFO) inhibitors such as piperonyl butoxide and cobaltous chloride. The purpose of this study was to determine the effect of phenobarbital, a MFO inducer, on cephaloridine nephrotoxicity in rats and rabbits. Phenobarbital induced rabbit renal MFO activities and also potentiated cephaloridine toxicity in rabbit kidneys. In contrast, a similar treatment with phenobarbital produced little effect on rat renal MFO activities and did not alter cephaloridine nephrotoxicity in rats. These results suggested that cephaloridine may have to be bioactivated within the kidney prior to producing toxicity. However, a higher renal cortical concentration of cephaloridine was detected in phenobarbital-treated rabbits. This higher concentration appeared to be due to a greater ability of renal cortical cells to accumulate cephaloridine. Therefore, rather than as a result of enzyme induction, the potentiating effect of phenobarbital on cephaloridine nephrotoxicity might be due to the increased renal cortical accumulation of the parent drug, cephaloridine.     

Measurements of weight and activity in male mice following inhalation of cannabis smoke in a controlled smoke exposure chamber

A smoke exposure device delivering marijuana smoke to mice is described. Standardized smoking conditions were achieved with this unit yielding a concentration of 0.123 mg/liter of delta-9-tetrahydrocannabinol in air. A significant (p < 0.05) decrease in locomotor activity in treated animals was seen following the fourth treatment in a 21-day study where animals were exposed three times weekly for 3 weeks. A significant decrease in body weight for marijuana-exposed animals was also noted. In another study, animals were exposed daily for 7 days. Locomotor activity was significantly decreased in marijuana-exposed animals on Days 6 and 7. There was no significant change in body weight. Following removal from the exposure chamber, the marijuana-exposed animals showed transient hyperactivity (1–3 min) followed by a period of depressed activity lasting 1 hr. Some tolerance to the placebo smoke was seen after the fourth treatment in both studies. Cumulative effects were seen following repeated exposures. These preliminary data suggest that inhalation of marijuana smoke will initiate behavioral changes in mice.     

Interactions of chlorpheniramine ethanol combinations: acute toxicity and antihistaminic activity

Significant toxicologic and pharmacologic interactions occurred between chlorpheniramine maleate and 25% $\text{v}\text{v}$ ethanol at several dosage combinations. Conditions of both independence and antagonism of acute toxicity were observed in LD50 determinations of chlorpheniramine-ethanol combinations in mice, and confirmed expected results based on the toxicologic pattern of the agents when administered singly. Enhancement of the antihistaminic action of chlorpheniramine by ethanol was demonstrated during histamine-aerosol challenge studies in guinea pigs.     

Early damage indicators in the lung: V. Biochemical and cytological response to NO2 inhalation

In an extension of earlier work on the usefulness of analysis of pulmonary lavage fluid as a probe to detect lung injury, we have examined lavage fluid from animals with a multifocal, terminal bronchiolitis induced by exposure to an oxidant gas. Syrian hamsters were exposed to concentrations of 0, 12, 17, and 22 ppm NO₂ gas for 48 hr. Bronchopulmonary lavage fluids were profiled biochemically and cytologically to determine (1) the indicators of a multifocal, deep lung injury that could be detected in the lung washings and (2) the lowest level of this type of injury that could be detected by the lavage fluid screen. Lung homogenates were assayed for the enzymatic activities measured in lavage fluid and the lungs were evaluated histologically. Highest response for all parameters measured was at 2 days (end of the exposure) when the lavage fluid showed dose-dependent elevations in lactate dehydrogenase, alkaline phosphatase, acid phosphatase, glutathione reductase, and glutathione peroxidase activities, sialic acid, and total protein content, as well as increases in macrophage and neutrophil cell counts. By far the most sensitive indicator of this type of injury, as measured by the lavage fluid screen, was the neutrophil cell count, which showed a 10-fold increase even at the lowest level of exposure. The greatest change seen in the biochemical parameters measured in lavage fluid was the increase in sialic acid and protein content. There was good correlation between the degree of alteration of biochemical and cytologic indicators of injury seen in the lavage fluid and the morphological alterations seen in tissue.     

The interaction of hepatic microsomal cytochrome P-450 with fluroxene (2,2,2-trifluoroethyl vinyl ether) in vitro.

The anaesthetic agent fluroxene (2,2.2-trifluoroethyl vinyl ether) and a closely related compound 2,2,2-trifluoroethyl ethyl ether (TFEE) interact with the cytochromc P-450 component of isolated rat hepatic microsomcs to produce a type I difference spectrum. The extent of the absorbance difference (ΔA) between λ_max (390 nm) and λ_min (420 nm) produced with fluroxene or TFEE is dependent on the concentration of the anaesthetic agent and the extent and type of prior induction of the microsomes. Induction of cytochrome P-448 with 3-methylcholanthrene (MC) or 3.4-benzpyrene (BP) does not affect the magnitude of the maximal absorbance difference spectrum (ΔA_max) relative to uninduced microsomes. In contrast, phenobarbital (PB) induced microsomes exhibit ΔA_max values with either anaesthetic agent which, relative to controls, arc increased approximately in proportion to the increase in the level of total type P-450 cytochromes. The K_s values for the binding of fluroxene and TFFE to all microsomal preparations are 9.3 × 10⁴ M and 1.7 × 10^?3 respectively. Both anaesthetics are metabolized by hepatic microsomal cytochrome P-450 as evidenced by enhanced carbon monoxide-inhibitahic NADPH oxidation in the presence of these compounds. The maximum velocities of NADPH consumption in the presence of cither anaesthetic are unaffected by induction with BP or MC but are increased approximately 3-fold following induction of cytochrome P-450 with PB. For fluroxene metabolism by all microsomes K_m was determined to be 8.4 × 10⁴ M. Determination of K_m values for TFEE metabolism is more complex as biphasic effects are observed with some systems. We conclude that fluroxene and TFEE bind to cytochrome P-450 and are metabolized but that TFEE is a poorer substrate. In contrast cytochrome P-448 neither binds nor metabolizes either anaesthetic. Since K_m and K_s values for fluroxene are the same we conclude that the rate-limiting step of its metabolism occurs at a step after the binding of fluroxene to ferricytochrome P-450.     

[14C]Methyl chloroform (1,1,1-trichloroethane): Pharmacokinetics in rats and mice following inhalation exposure

Studies on the pharmacokinetics of [¹⁴C]methyl chloroform (1,1,1-trichloroethane) in male Fischer 344 rats and B6C3F1 mice were undertaken to characterize the disposition of the inhaled chemical over a wide range of exposure concentrations. The animals were exposed to 150 or 1500 ppm of [¹⁴C]methyl chloroform vapor for 6 hr and the elimination of ¹⁴C activity was followed for 72 hr. Following exposure to either concentration of methyl chloroform, both species excreted >96% of the total recovered radioactivity during the first 24 hr. The major route of elimination of methyl chloroform was via exhalation of unchanged chemical in the expired air which constituted approximately 94–98% of the total recovered radioactivity in rats and 87–97% in mice at 150 and 1500 ppm, respectively. Mice were found to eliminate methyl chloroform in the expired air more rapidly than did rats. The remaining radioactivity (approximately, 2–13%) was detected as metabolized methyl chloroform in the expired air (¹⁴CO₂) and as nonvolatile radioactivity in the urine, feces, carcass, and cage wash. Although mice were found to metabolize two to three times more methyl chloroform on a body weight basis, the biotransformation of methyl chloroform was shown to be a saturable, dose-dependent process in both species. Since the biotransformation of methyl chloroform occurred to such a limited extent, saturation of its metabolism did not impact markedly on the distribution or elimination of the parent chemical. The body burden, end-exposure blood level, and tissue concentration of methyl chloroform were found overall to increase in direct proportion with the exposure concentration. [¹⁴C]Methyl chloroform was more concentrated in the fat of both species than in the liver or kidneys immediately after exposure. However it was rapidly cleared from the fat so that by 24 hr <2% of the initial radioactivity remained. Thus, methyl chloroform shows little potential for significant bioaccumulation in rodents.     

Reproductive toxicity of dimethyl methyl phosphonate (DMMP) in the male Fischer 344 rat

Dimethyl methyl phosphonate (DMMP) has been considered for use by the U.S. Armed Forces as a nerve gas simulant in a variety of experimental situations to simulate the physical properties of nerve gases, but not the neurotoxic properties. Dimethyl methyl phosphonate is also used as a flame retardant for urethane foams and polyester resins. This study was conducted to determine the reproductive toxicity of DMMP after subchronic dosing. DMMP was administered to male Fischer 344 rats by gavage 5 days/week for 90 days at dosages of 0, 250, 500, 1000, and 2000 mg/kg, and all animals survived this dosing schedule. At Day 84, the rats were mated to untreated female Fischer 344 rats. There was a dose-related decrease in sperm count, sperm motility, and the male fertility index. The male fertility index was 70, 75, 60, 40, and 0% in the 0, 250, 500, 1000, and 2000 mg/kg dose groups. DMMP acted as a dominant lethal mutagen as demonstrated by an increase in the number of resorptions with increasing doses of the drug. The percentage of resorptions in the control group was 6.1% and increased to 14.9, 37.8, and 79.1% in the 250, 500, and 1000 mg/kg groups, respectively. The testes of the male rats were examined histologically to determine the relationship between reproductive function and pathologic abnormalities. DMMP altered reproductive function at all dose levels, while histologic abnormalities of the testis were seen only in the high-dose group. Changes in the testes of the high-dose animals were characterized by lack of spermatogenesis or by degeneration, vacuolization, and necrosis of cells in the spermatogenic tubules. Histopathologic abnormalities of the kidney were seen in some animals from each of the dosed groups and microscopic changes of the prostate were seen in some of the high-dose animals.     

Toxicity of topical polyethylene glycol

An animal model was developed to study the potential toxicity resulting from repeated, topical applications of a polyethylene glycol-based antimicrobial cream. Applications of this cream to open wounds in rabbits produced the same syndrome observed in the burn patients treated with this agent. This syndrome was characterized by (1) elevated total calcium, (2) elevated osmolality gap, (3) high anion gap metabolic acidosis, and (4) renal failure. Ten of twelve treated animals died within one week of therapy. This syndrome appears to result from the absorption of polyethylene glycols and their metabolism to nephrotoxic compounds and to mono- and diacids. We propose that the increased serum osmolality reflects the absorption of glycols and their presence in the circulation, while the acidosis reflects the presence in plasma of mono- and diacid metabolites of the glycols. The diacid metabolities of low-molecular-weight polyethylene glycols are excellent calcium chelators and can account for the hypercalcemia. Finally, we suggest that polyethylene glycol metabolites produce renal destruction via mechanisms similar to those involved in the renal failure associated with ethylene glycol poisoning.