Disposition of tetrachloro(14C)ethylene following oral and inhalation exposure in rats

Tetrachloro[¹⁴C]ethylene (Perc) was administered to adult, male Sprague-Dawley rats by gavage (1 or 500 mg/kg) or by inhalation (10 or 600 ppm, 6 hr duration). Within 72 hr following oral administration of 1 mg/kg or inhalation of 10 ppm [¹⁴C]Perc, approximately 70% of the body burden of radioactivity was excreted in expired air as Perc, 26% as ¹⁴CO₂ and nonvolatile metabolites in urine and feces, and 3 to 4% remained in the carcass. After oral administration of 500 mg/kg or inhalation of 600 ppm [¹⁴C]Perc, 89% of the radioactivity was recovered in expired air as Perc, 9% as ¹⁴CO₂ and urinary and fecal metabolites, and 1 to 2% remained in the carcass. The major urinary metabolite of Perc was identified as oxalic acid. Pulmonary elimination of Perc was monophasic with a half life ($\text{t}\text{1}\text{2}$) of approximately 7 hr independent of dose or route of administration. Radioactivity remaining in the carcass 72 hr after exposure by either route was primarily distributed within liver, kidney and fat tissue. In liver, 85 to 90% of the total radioactivity was cleared within 72 hr following inhalation exposure to 10 or 600 ppm. Nonextractable radioactivity, either bound or incorporated into hepatic macromolecular material, was cleared at a slower rate. The tissue concentration of nonextractable radioactivity was dependent upon body burden and metabolic capacity but apparently not upon route of administration. Thus, the data indicate that disposition of Perc is a saturable, primarily dose-dependent process in rats.     

Temperature-dependent disposition of [14C]benzo(a)pyrene in the spiny lobster, Panulirus argus

[¹⁴C]Benzo(a) pyrene (BP) (1 mg/kg) was administered by intracardiac injection to groups of spiny lobsters which were killed at various times up to 7 weeks after dosing. Tissues and fluids were evaluated for BP-derived radioactivity. Two studies were conducted in successive summer and winter seasons, when seawater temperatures throughout were 26.5 to 29.0 and 13.5 to 16.5°C, respectively. Highest concentrations of BP-derived radioactivity were found in the hepatopancreas, stomach, intestine, intestinal contents, and the green gland. After an initial distribution phase, the dose was lost from the lobsters in a log linear manner. The elimination half-lives for overall elimination of BP-derived radioactivity were 1.11 weeks in the warmer (summer) and 2.25 weeks in the colder (winter) water. Similarly, for individual organs, elimination was more rapid in the warmer water. For the hepatopancreas, green gland, intestine, and tail muscle, respective $\text{t}\text{1}\text{2}$ values (week) were 1.02, 1.26, 1.71, and 1.42 in the summer and 2.50, 1.50, 5.04, and 2.11 in the winter. There was no suggestion of tissue accumulation of BP-derived radioactivity. HPLC analysis of hepatopancreas samples showed that, in summer, unmetabolized BP concentrations fell rapidly, accounting for only 5% of the total label in the hepatopancreas by 3 days. The fall in unmetabolized BP was accompanied by approximately equal increases in the percentages of both polar metabolites and conjugates. Although the time curve for metabolism of BP in the hepatopancreas was not studied in winter, the metabolic capacity was such that, by 3 days after the dose, only 5% of the ¹⁴C present in hepatopancreas was unmetabolized BP. Thus, it appears that, for this dose of BP, the more rapid elimination of ¹⁴C in summer was due to a more rapid excretion of metabolites, and not to increased metabolism of BP.     

Identification of turkey biliary metabolites of ractopamine hydrochloride and the metabolism and distribution of synthetic [14C]ractopamine glucuronides in the turkey

1. The bile duct cannulated turkey poult (n = 3) dosed orally with [¹⁴C]ractopamine HCl {(1R*,3R*),(1R*,3S*)-4-hydroxy-α-[[[3-(4-hydroxy[¹⁴C]phenyl)-1-methylpropyl]-amino]methyl]-benzenemethanol hydrochloride; 19.9 mg; 9.28 μCi] excreted 37.46 12.1% (mean ± SD) of the administered radioactivity in bile by 24 h post-dosing. 2. A mono-glucuronide, conjugated at C-10 (the methylpropylamino phenol) of ractopamine, accounted for 76.6% of biliary radioactivity. 3. Urine collected from the colostomized turkey poult (n = 3) orally dosed with synthetic [¹⁴C]ractopamine-glucuronides (10.1 mg; 3.6 μCi) contained 11.96 1.0% (mean ± SD) of the administered radioactivity 24 h after dosing, indicating that some absorption of radioactivity occurred. Faeces contained 60.6% of the administered radioactivity and carcasses (with gastrointestinal tracts) contained 23.3% of the starting radioactivity. 4. Five colostomized poults were fitted with bile duct cannulas and were dosed intraduodenally with 10.2?mg (3.6 μCi) synthetic [¹⁴C]ractopamine-glucuronides. Urine and bile contained 15.5 ± 2.2 and 16.8 ± 2.1% respectively of the administered radiocarbon by 24 h post-dosing. Faeces contained 54.3% of the administered radioactivity. Total absorption of the dosed radioactivity averaged 33.4%. 5. Bile and urine collected from the colostomized, bile-duct cannulated bird contained mainly ractopamine glucuronides. Indirect evidence suggests that the dosed ractopamine glucuronides were not absorbed intact.     

Tissue distribution,excretion, and metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the Golden Syrian hamster

The hamster has been reported to be the least sensitive mammalian species to the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The fate of a single dose of [³H]- or [¹⁴C]TCDD (650 μg/kg, ip or po) was assessed in male hamsters for up to 35 days following treatment. The greatest content (percentage dose/g tissue) of radioactivity was found in the liver, adipose tissue, and adrenals. The radioactivity in liver and adipose tissue was identified as unmetabolized TCDD. The rate of ³H or ¹⁴C elimination in urine and feces suggested a first-order process. Similar half-life of elimination ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$) values of 12.0 ± 2.0 and 10.8 ± 2.4 days (mean ± SD) were obtianed with ip administered [³H]- and [¹⁴C]TCDD, respectively. With both [³H]- and [¹⁴C]TCDD, approximately 35 and 50% of the radioactivity was eliminated in urine and feces, respectively. The $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ for po administered [³H]TCDD was 15.0 ± 2.5 days. High-pressure liquid chromatography of the urine and bile of animals receiving [¹⁴C]TCDD revealed one major and several minor radioactive peaks, none of which corresponded to [¹⁴C]TCDD. The apparent absence of TCDD metabolites in extracts of liver or adipose tissue indicates that the biotransformed products of TCDD are readily excreted in urine and bile. The enhanced rate of metabolism and excretion of TCDD in hamsters relative to other species may in part contribute to, but not totally explain its unusual resistance to TCDD toxicity.     

Species differences in the acute toxicity and tissue distribution of DDT in mice and hamsters

Orally administered DDT is acutely neurotoxic to the Swiss mouse and the Syrian golden hamster, but the latter is affected only at much higher doses. The central nervous system of each species is equally sensitive to DDT, since brain concentrations of DDT were similar after lethal doses. However, after an oral dose of 500 mg/kg, the DDT content of mouse brain was twice the value of that found in the hamster. This could not be explained by a species difference in absorption, metabolism or excretion of DDT, and is probably due to differences in the permeability of the blood/brain barrier to DDT. When animals were maintained on 250 ppm dietary DDT for 6 weeks, the total fat and liver residues were 7–8 times higher in the mouse than in the hamster, the mouse liver containing relatively more DDE and the hamster more DDD. The rate of urinary excretion of radioactivity was similar in control animals after [¹⁴C]DDT administration; dietary DDT pretreatment stimulated [¹⁴C]DDT metabolism and excretion in the hamster but had little effect in the mouse. Mice also consumed 3 times more DDT-containing food/kg body weight than the hamster, and these differences account for the higher tissue residues in the mouse. The species differences in DDT metabolism and tissue metabolites are discussed with reference to the difference in tumorigenic response to DDT in the mouse and hamster.     

Metabolic fate of [1-14C]isobutyric acid in the rat.

Isobutyric acid (IBA) has potential use as a fungistat for the storage of moist grain. Since a complete accounting of the fate of IBA has not been reported, the metabolic fate of [1-¹⁴C]IBA was investigated. [1-¹⁴C]IBA was administered by gavage to male Charles River CD rats at doses of 4, 40, and 400 mg/kg body weight and to female rats at 400 mg/kg. All rats showed a similar excretion pattern. [1-¹⁴C]IBA was eliminated rapidly in the breath as expired ¹⁴CO₂. At 4 hr, 75.4, 83.3, and 66.7% of the dose was eliminated in the breath by male rats dosed with 4, 40, or 400 mg/kg, respectively. At 48 hr, 85–90% of the dose was eliminated in the breath. Urinary radioactivity averaged 3.5% of the dose, with about $\text{2}\text{3}$ of the radioactivity present as urea. Fecal radioactivity was less than 1% of the dose. The excretion of radioactivity by female rats was similar to that of male rats dosed with [1-¹⁴C]IBA. Isobutyric acid disappeared rapidly from the plasma of rats dosed by gavage with 400 mg/kg. These studies show that IBA is rapidly metabolized to CO₂ and its use as a feed fungistat is unlikely to contribute to the endogenous levels of IBA in the flesh, eggs, or milk or grain-consuming animals.     

Uptake and metabolic rate of liposome-entrapped [U-14C]glutamate in rats

The metabolic fate of [U-¹⁴C]glutamate administered intravenously to rats in aqueous solutions or entrapped in vescicles of phospholipids extracted from rat brain has been studied. When [U-¹⁴C]glutamate was administered entrapped in liposomes, higher serum radioactivity levels and higher radioactivity uptake by liver and brain were observed. Rats treated with [U-¹⁴C]glutamate entrapped in liposomes exhibited an increased glutamate oxidation shown by increased expired [¹⁴C]CO₂ and a modified elimination of the radioactivity in urine.     

Excretion of THC and its metabolites in ewes' milk

After single iv injections of either 0.02 mg/kg or 1 mg/kg of $\text{[}{}^{14}\text{C}\text{]Δ}{}^9\text{-}\text{tetrahydrocannabinol}$, [¹⁴C]THC, to lactating ewes, radioactivity was detected in the milk at all subsequent time intervals tested (4–96 hr). Radioactivity was found in unchanged THC as well as in various unidentified metabolites. Only about 15% of the administered radioactivity was excreted by the ewes in the first 48 hr; most of this was in the urine and feces. Radioactivity appeared in the feces and urine of a lamb suckling milk from a ewe injected with [¹⁴C]THC, indicating transfer of THC and its metabolites via the milk. These results confirm previous literature reports indicating slow elimination of THC, and show that milk is an additional route of excretion.     

Metabolism of Nicotine by the Isolated Perfused Dog Lung

Abstract

1. Metabolism of [¹⁴C]nicotine has been studied in the isolated perfused dog lung. [¹⁴C]Nicotine, 50 μg every 30 s for 10 min administered via the pulmonary artery, undergoes first pass metabolism to a small extent. [¹⁴C]Cotinine was detected in the venous blood. Of the injected activity, 6% was in the lung at the end of experiment; 60% being present as [¹⁴C]nicotine and 20% as [¹⁴C]nicotine-1′-oxide.

2. When [¹⁴C]nicotine was administered in cigarette smoke a greater degree of metabolism was observed at first pass. Pyrolysis products of [¹⁴C]nicotine also were present in the venous blood. Lungs after smoke exposure contained 30% of administered radioactivity, with a substantial proportion of [¹⁴C]-nicotine-1′-oxide.

3. Administration of [¹⁴C]nicotine-labelled smoke to lung preparations, on closed circuit, gave significant amounts of [¹⁴C]cotinine and other metabolites over a 2 h period. Lung tissue contained approx. 40% of injected dose, of which 25% only was [¹⁴C]nicotine. Large proportions of [¹⁴C]cotinine and [¹⁴C]-nicotine-1′-oxide were present but 45% of the activity was present as other unidentified pyrolysis products. [¹⁴C]Demethyl cotinine was detected.     

Percutaneous absorption of hexachlorophene in the rat.

[¹⁴C]-hexachlorophene was applied to intact, clipped skins of adult rats in four different solvents and an aqueous detergent solution. As much as 55% of the applied radioactivity was absorbed through the skin in a 24-hr period. Dimethyl sulfoxide enhanced absorption of the germicide to the greatest extent and aqueous sodium lauryl sulfate (1%, $\text{w}\text{v}$) was the least effective. With both adult and weanling rats, the first measurable amount of radioactivity appeared in the venous blood in less than 1.5 hr, and maximum values were attained 12 hr after topical application of [¹⁴C]hexachlorophene. Approximately 27% of the applied radioactivity remained bound to the skin after 4 and 24 hr and was not removed by washing with acetone. Distribution of radioactivity in rats 8 and 24 hr after topical application of [¹⁴C]hexachlorophene was similar in weanling and adult rats. Most of the absorbed radioactivity appeared in the plasma, liver, small intestine, caecum, stomach, kidney, urine, and feces.     

Fate of n-butanol in rats after oral administration and its uptake by dogs after inhalation or skin application.

n-[1-¹⁴C]Butanol was mixed with corn oil and administered by gavage to male Charles River C.D. rats in doses of 4.5, 45, or 450 mg/kg of body wt. Rats dosed with 450 mg/kg excreted 83.3% of the dose as ¹⁴CO₂ at 24 hr; 4.4% was excreted in the urine; less than 1% was eliminated in feces and 12.3% remained in the carcass. n-[1-¹⁴C]Butanol was excreted in the urine apparently as an O-sulfate and as an O-glucuronide, both of which accounted for 75% of the radioactivity. Urea accounted for the remainder. Rats dosed with 4.5 or 45 mg/kg showed a similar excretion pattern to that of rats dosed with 450 mg/kg. Excretion studies were performed to quantify the percutaneous absorption of n-butanol in male beagle dogs. n-[1-¹⁴C]Butanol was absorbed through the skin of dogs at a rate of 8.8 μg min^?1 cm^?2. Dogs exposed by inhalation to 50 ppm of n-butanol vapor absorbed about 55% of the inhaled vapor. The elimination of n-butanol in the postexposure breath was relatively low compared to the quantity absorbed during the exposure. Dogs dosed with ethanol (200 mg/kg, po) and then exposed to 50 ppm of n-butanol vapor for 6 hr showed no evidence that the exposure to n-butanol vapor inhibited the metabolism of ethanol. These findings suggest that occupational exposure to n-butanol vapor at the current threshold limit value is not likely to affect the metabolism of low doses of ethanol taken concurrently.     

Inhalation studies on the biotransformation and elimination of [C]trichlorofluoromethane and [C]dichlorodifluoromethane in Beagles

The possible biotransformation of trichlorofluoromethane (FC-11) and dichlorodifluoromethane (FC-12) was investigated in 4 male and 2 female adult Beagles after a short (6- to 20-min) inhalation. Dogs were anesthetized with ketamine and succinylcholine, intubated, and ventilated artificially. Trichlorofluoromethane (1000–5000 ppm, v/v) or dichlorodifluoromethane 38000–12,000 ppm, v/v) containing up to 180μ Ci of [¹⁴C]fluorocarbon was delivered from 110-liter Teflon bags, and all exhalations were collected via a nonrebreathing valve in similar bags for 1 hr. Venous blood samples were withdrawn at appropriate times and assayed for fluorocarbon-associated radioactivity. Exhalation bags were assayed for [¹⁴C]fluorocarbon and ¹⁴CO₂. Urine was collected for up to 3 days and assayed for ¹⁴C metabolites as nonvolatile radioactivity. In some experiments animals were sacrificed 24 hr after exposure and tissues were removed for determination of nonvolatile radioactivity. Essentially all of the administered (inhaled) fluorocarbon was recovered in the exhaled air within 1 hr. Only traces of radioactivity were found in urine or exhaled carbon dioxide. All tissues contained measurable concentrations of nonvolatile radioactivity 24 hr after exposure but together represented less than 1% of the administered dose. It is not possible to determine if these trace levels are associated with metabolites of the fluorocarbons or with the unavoidable radiolabeled impurities present in the administered gas mixture. Neither phenobarbital pretreatment (60 mg/day for 3 days) nor prolonged exposure (50–90 min) produced any alteration of these results. Thus, it can be concluded that FC-11 and FC-12 are relatively refractory to biotransformation after a short inhalation exposure and that they are rapidly exhaled in their unaltered chemical form.     

The Metabolic Fate of [Vinyl-I-14C]Dichlorvos in the Rat after Oral and Inhalation Exposure

Abstract

1. [Vinyl-1-¹⁴C]Dichlorvos is rapidly metabolized when administered orally to the rat, the major metabolite being [¹⁴C]carbon dioxide.

2. Much of the administered radioactivity is incorporated into the pathways of intermediary metabolism and thus the residual radioactivity associated with the carcass four days after the treatment is relatively high. Most of the radioactivity retained in the livers of treated animals has been identified as [¹⁴C] glycine and [¹⁴C]serine, incorporated into liver protein. It is probable that the amino acids were synthesized via dichlorvos, dichloroacetaldehyde and glyoxylate.

3. At least nine radioactive metabolites were found in urine; those identified were hippuric acid (8.3% of urinary radioactivity); desmethyldichlorvos (10.9%), dichloroethanol glucuronide (27%) and urea (3.1%).

4. The rapid detoxification of dichlorvos can be attributed to hydrolytic and demethylation reactions, leading to dichloroacetaldehyde, which is then partly reduced to dichloroethanol and excreted as the glucuronide and also partly dechlorinated and incorporated into a two-carbon biosynthetic pathway.

5. When [¹⁴C]dichlorvos was inhaled by rats, the excretion and retention data, together with analysis of radioactive metabolites in the liver, and in urine, indicated that the gross pathways of metabolism did not appreciably differ from those observed after oral administration.     

Oral bioavailability and disposition of sulphadimethoxine in lobster,Homarus americanus,following single and multiple dosing regimens

1. Single and multiple oral doses of sulphadimethoxine or sodium sulphadimethoxine were administered by gavage to lobster, and sequential samples of haemolymph were taken for analysis of parent sulphadimethoxine. Single doses of sodium sulphadimethoxine were given over a dose range of 14–70mg/kg. Five 42-mg/kg doses of sulphadimethoxine on alternate days were administered for the multiple-dose studies. Some experiments were conducted with radiolabelled (³⁵S or ¹⁴C) sulphadimethoxine, and the tissue distribution of radioactivity was determined at different killing times.

2. Pharmacokinetic parameters were obtained by fitting sulphadimethoxine concentrations in haemolymph to a one-compartment model. Oral bioavailability at the 42-mg/kg dose, calculated from the area under the haemolymph concentration-time curve (AUC) relative to the AUC from intravascular administration, was between 47 and 52% for single or multiple doses of the free drug. The bioavailability of sodium sulphadimethoxine was dose dependent, at 97% for the 14mg/kg dose, and 25% for the 70-mg/kg dose. The low bioavailability at the high dose probably resulted from poor absorption due to the limited solubility of sulphadimethoxine at the low pH of the lobster gastrointestinal tract.

3. Sulphadimethoxine and several polar metabolites were excreted in lobster urine. Polar metabolites were also found in the hepatopancreas and haemolymph. At least 20% of the 42-mg/kg dose was metabolized. The major vertebrate metabolite of sulphadimethoxine, N-acetylsulphadimethoxine, was a very minor metabolite in lobster. The identities of the polar metabolites were not established.

4. Elimination of sulphadimethoxine residues from muscle to >0.1 μg sulphadimethoxine equivalents/g tissue required 40 days after a single dose, or 44 days after the last of multiple doses. Concentrations of sulphadimethoxine residues in all other tissues were always greater than muscle concentrations. Data showed that sulphadimethoxine residues were very persistent in lobster tissues.     

Age-dependent retention of [14C]DDT in the brain of the postnatal mouse

Postnatal mice, at the age of 0 (newborn), 3, 7, 10, 15, 20 and 55 days, were given a single administration of dichlorodi[U-¹⁴C]phenyltrichloroethane ([¹⁴C]DDT; 1.48 MBq/kg body wt.) per os. They were killed 24 h or 1 week post-treatment and the amount of radioactivity in the brain was measured. The most pronounced retention was found in mice receiving [¹⁴C]DDT on the tenth postnatal day. The activity found after 1 week was as high as that observed after 24 h, and it was also highest in this age category even though older mice displayed a higher activity 1 day after administration.     

Paraquat disposition in rats, guinea pigs and monkeys

LD50 doses of ¹⁴C-labeled paraquat were administered to rats, guinea pigs and monkeys by gavage, and radioactivity was determined in excreta and tissues. Rat urine was analyzed for paraquat metabolites by thin-layer chromatography. [¹⁴C]Paraquat was absorbed from the gastrointestinal tract and reached highest serum values 0.5–1 hr after administration. Disappearance of [¹⁴C]paraquat from serum was characterized by a rapid initial decline followed by a prolonged slow decline. Tissue paraquat values were higher than serum values in rats and guinea pigs. Relative to other tissues, paraquat accumulated transiently in the lung and reached peak concentration 32 hr after administration. In rats a major portion of administered paraquat was not absorbed from the gastrointestinal tract. At 32 hr after paraquat, 52% of the administered dose remained in the gastrointestinal tract and 17 and 14% of the administered dose was excreted in the feces and urine, respectively. No radioactivity was recovered in expired air or flatus. Excretion of paraquat in urine and feces was prolonged in all species. In monkeys paraquat was measured in urine and feces 21 days after administration. Chromatography of urine from [¹⁴C]paraquat-treated rats revealed no metabolites. The primary pathologic changes induced by paraquat in the lung may be related to the transient uptake of the chemical by that organ.     

The absorption,tissue distribution,and excretion of dodecyldimethylamine oxide (DDAO) in selected animal species and the absorption and excretion of DDAO in man

The absorption tissue distribution, and excretion pattern of [methyl-¹⁴C]DDAO and [1-dodecyl-¹⁴C]DDAO administered orally or cutaneously to rats, mice, and rabbits were investigated. The excretion pattern of radioactivity from [1-dodecyl-¹⁴C]DDAO administered orally and cutaneously to man was also investigated. An oral dose of DDAO is rapidly and extensively absorbed and excreted by rats and man. Peak tissue levels of radioactivity resulting from oral administration of [methyl-¹⁴C]DDAO to rats occur within 1 hr after dosing. Cutaneously administered DDAO is absorbed by man, rats, rabbits, and mice. In man, the rate of DDAO absorption through the skin is at least one order of magnitude less than that observed in rats, mice, and rabbits.     

Comparative Studies on the Metabolic Disposition of 8-Chloro-6-pheny1–4H-s-triazolo[4,3-a][1,4]benzo-diazepine (D-40TA) and Nitrazepam after Single and Repeated Administration in Rats

Abstract

1. Orally administered D-40TA was absorbed by rats with a maximum blood level at 30 min and a half-life of 60 min. The blood level of orally administered nitrazepam reached a plateau which persisted for 90 min and then declined with a half-life of 90 min.

2. Both D-40TA and nitrazepam crossed the blood-brain barrier of rats. The 1-oxo metabolite of D-40TA is pharmacologically active, and also readily entered the brain.

3. Orally administered D-40TA and nitrazepam were eliminated in urine and faeces over 3 days, the larger part in faeces. In both cases, about 90% of the dose of radioactivity was eliminated from the body during the first 2 days after administration.

4. After intravenous injection of either [¹⁴C]D-40TA or [¹⁴C]nitrazepam, the radioactivity was excreted in bile at the same rate, 69 and 64% of the dose being recovered from the 24 h-bile, respectively. The biliary metabolites of both benzodiazepines underwent entero-hepatic cycling.

5. After daily oral administration of [¹⁴C]D-40TA or [¹⁴C]nitrazepam, the cumulative excretion closely paralleled the dosage of radioactivity. For both drugs, excretion was complete within 3 days of discontinuing medication. During repeated administrations of the labelled drugs, no increase in concn. of blood radioactivity 1 h after dosing was observed. With [¹⁴C]D-40TA-treated rats, most of the radioactivity still in the body 24 h after administration was recovered from the gastro-intestinal contents; only small amounts were in tissues. Dosing of [¹⁴C]D-40TA for 7 days caused no increase in tissue levels of radioactivity, except in the liver, where the radioactivity increased to about twice the level noted after a single administration.     

Hepatic macromolecular binding following exposure to vinyl chloride

Covalent binding of radioactivity to hepatic macromolecules in rats exposed to ¹⁴C-labeled vinyl chloride (VC) was studied to determine if VC-induced carcinogenesis may be related to electrophilic alkylation of macromolecules in vivo. Male Sprague-Dawley rats were exposed to 1, 10, 25, 50, 100, 250, 500, 1000, or 5000 ppm of [¹⁴C]VC for 6 hr. Following exposure, radioactivity covalently bound to hepatic macromolecules and purified nucleic acids (RNA, DNA) was determined. The total amount of [¹⁴C]VC metabolized and hepatic glutathione (GSH) content were also determined. The total amount of radioactivity bound to macromolecules in the liver did not increase proportionately to the increase in the exposure concentration of VC. A disproportionate decrease in macromolecular binding was observed as the concentration of VC increased. The covalent binding to hepatic macromolecules was related to the amount of VC metabolized. At exposures greater than 50 ppm, the amount of ¹⁴C bound to macromolecules in the liver correlates with induction of hepatic angiosarcoma. There was no detectable binding of radioactivity to either DNA or RNA in the liver. Hepatic glutathione content was significantly depressed only at exposure concentrations greater than 100 ppm.     

Studies on the respiratory uptake and excretion and the skin absorption of methyl n-butyl ketone in humans and dogs

Methyl n-butyl ketone (MnBK) has produced peripheral neuropathy in experimental animals and is implicated in an occupationally produced neuropathy. Since occupational exposure to MnBK is by inhalation or skin contact, both the absorption and elimination of MnBK vapor and its absorption through skin were investigated. Studies were carried out first with male beagle dogs and subsequently with human volunteers. Humans exposed for 7.5 hours to 10 or 50 ppm or for 4 hr to 100 ppm of MnBK vapor absorbed between 75 and 92% of the inhaled vapor. Unchanged MnBK was not eliminated extensively in the postexposure breath or in urine. 2,5-Hexanedione, a metabolite of MnBK known to be neurotoxic in rats, was found in the serum of humans exposed to either 50 or 100 ppm of MnBK. The absorption and elimination of MnBK in dogs was similar to that observed in humans. The skin absorption of [1-¹⁴C]MnBK or a $\text{9}\text{1}$ ($\text{v}\text{v}$) mixture of methyl ethyl ketone $\text{(MEK)}\text{[1-}{}^{14}\text{C]MnBK}$ was determined by excretion analysis. Two volunteers exposed by skin contact to [1-¹⁴C]MnBK absorbed 4.8 μg min^?1 cm^?2 and 8.0 μg min^?1 cm^?2, respectively. Skin exposure to $\text{MEK}\text{[1-}{}^{14}\text{C]MnBK}$ resulted in the respective absorption of 4.2 and 5.6 μg min^?1 cm^?2 by two individuals. Two volunteers given an oral dose of [1-¹⁴C]MnBK (2 μCi; 0.1 mg/kg) excreted 49.9 and 29.0% of the dose, respectively, as respiratory ¹⁴CO₂ within 3 to 5 days and 27.6 and 25.0% of the dose, respectively, in urine within 8 days. Both [1-¹⁴C]MnBK and $\text{MEK}\text{[1-}{}^{14}\text{C]MnBK}$ were absorbed through the skin of dogs. These findings show that MnBK is readily absorbed by the lungs, the gastrointestinal tract, and through the skin, is not eliminated extensively unchanged in breath or urine, and is metabolized to CO₂ and 2,5-hexanedione. Radioactivity derived from [1-¹⁴C]MnBK was excreted slowly by man, suggesting that repeated daily exposure to high concentrations of MnBK may lead to a prolonged exposure to neurotoxic metabolites.