The lack of effects of pretreatment with phenobarbital and chlorpromazine on the acute toxicity of benzene in rats

Female CD rats were injected ip daily for 3 days with either phenobarbital (75 mg/kg) or chlorpromazine (15 mg/kg). On the fourth morning the animals were either subjected to a 4-hr inhalation exposure of benzene or given an ip injection of 50% ($\text{v}\text{v}$) of benzene and mineral oil. Animals were injected with doses of 1, 2, 3 and 4 g benzene/kg body weight. In the inhalation studies, animals were exposed to 6 levels of benzene ranging from 11,500 to 15,500 ppm. The LD50 for animals injected with benzene and the LC50 for animals inhaling benzene were calculated for control groups and those pretreated with either phenobarbital or chlorpromazine. Neither the LD50 or the LC50 were affected by any of the treatment protocols. In order to determine that the pretreatment was stimulating benzene metabolism, a method for measuring benzene metabolism has been developed using [¹⁴C]benzene. These studies have shown that phenobarbital and 3-MC do induce benzene metabolism in the liver, that chlorpromazine slightly induces benzene metabolism in the lung, and that pretreatment by these compounds does not affect the acute inhalation toxicity or the ip toxicity of benzene.     

Pulmonary toxicity,hepatic, and extrahepatic metabolism of 2-methylnaphthalene in mice

Male mice ($\text{C57BL}\text{6J}$) were injected once ip with 0.1, 1, 100, 200, 400, 600, 800, or 1000 mg/kg of 2-methylnaphthalene dissolved in corn oil. After 24 hr, the animals were killed and the lungs, livers, and kidneys were prepared for light microscopy. In addition, some lungs were subjected to scanning and transmission electron microscopy. A dose of 200 mg/kg produced a bronchiolar necrosis which affected the nonciliated bronchiolar (Clara) cell; the parenchymal cells remained unaffected. At higher doses of 2-methylnaphthalene (800 mg/kg), in addition to the damaged Clara cell, severe damage to the upper respiratory tract was noted. No liver or kidney pathology was detected by light microscopy in animals treated with the highest dose. No cellular damage was noted in any organ at doses less than 200 mg/kg. Forty-eight hours after a dose of 200–1000 mg/kg of 2-methylnaphthalene, less pulmonary damage was detected by light microscopy. The metabolism of 2-methylnaphthalene was investigated in hepatic, pulmonary, and renal microsomes from $\text{C57BL}\text{6J}$ mice. Lung and liver microsomes produced three isomeric dihydrodiols of 2-methylnaphthalene as well as other monohydroxylated metabolites. Only trace amounts of these metabolites were produced by the kidney.     

Fate of (14C)vinyl chloride after single oral administration in rats.

Male rats were given single oral doses of 0.05, 1, and 100 mg/kg of [¹⁴C]vinyl chloride (VC), and the routes and rates of elimination of ¹⁴C activity followed for 72 hr. Following 0.05 and 1 mg/kg, excretion in the urine as nonvolatile metabolites and as ¹⁴CO₂ in expired air accounted for 59–68% and 9–13%, respectively of the administered dose. Only 1–2% of the dose was expired by the lungs as VC. Conversely, after 100 mg/kg, 67% of the dose was eliminated by the lungs as VC, while urinary nonvolatile metabolites and ¹⁴CO₂ comprised 11 and 3%, respectively. Pulmonary elimination after 100 mg/kg showed an apparent biphasic clearance with haif-times ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$) of 14.4 and 40.8 min for the respective fast and slow phases. Following 0.05 and 1 mg/kg the pulmonary clearance of VC was monophasic with $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ of 53.3 and 57.8 min. The percentage of the dose remaining in the carcass after 72 hr was 10, 11, and 2% for the 0.05-, 1- and 100-mg/kg doses, respectively. The urinary radio-activity was separated by high pressure liquid chromatography into three major metabolites. Two of the three major urinary metabolites have been identified as N-acetyl-S-(2-hydroxyethyl)-cysteine and thiodiglycolic acid by gas chromatography-mass spectrometry. The proportions of the urinary metabolites were not influenced by the dose. The fate of VC following an oral dose between 1 and 100 mg/kg was clearly dose-dependent. Consistent with our previous studies on the fate of VC following inhalation exposure in rats, the metabolism of VC appears to be a saturable process.     

Acute toxicity of oral diquat (1,1'-ethylene-2,2'-bipyridinium) in cynomolgus monkeys.

Single doses of 100, 200, 300, and 400 mg diquat ion/kg body wt were administered by stomach tube to cynomolgus monkeys. Within 4 days of dosing deaths occurred in $\text{1}\text{2}$, $\text{0}\text{4}$, $\text{1}\text{2}$, and $\text{2}\text{2}$ monkeys, respectively. All animals developed diarrhea and the most severely affected became comatose. The most important histopathological changes were necrosis of the epithelium and villi of the gastrointestinal tract and of the epithelium of the proximal and distal convoluted tubules of the kidneys.     

Acute toxicity of polyethylene glycol p-isooctylphenol ether in Syrian hamsters exposed by inhalation or bronchopulmonary lavage

Dose-response studies were conducted with Syrian hamsters exposed to polyethylene glycol p-isooctylphenyl ether (Triton X-100) via inhalation or bronchopulmonary lavage. Syrian hamsters were exposed to an aerosol of Triton X-100 with a mass median aerodynamic diameter of 1.5 μm and a concentration of 3.0 mg/liter. Estimated initial lung burdens of Triton X-100 ranged from 800 to 3100 μg. Hamsters were lavaged with concentrations of Triton X-100 ranging from 0.01 to 0.10% in isotonic saline resulting in initial lung burdens of Triton X-100 that ranged from 300 to 3200 μg. The $\text{LD}\text{50}\text{7}$ values were 1700 μg (1300–2100 μg, 95% confidence limits) for the inhalation study and 2100 (1900–2700) μg for the lavage study. The difference between the $\text{LD}\text{50}\text{7}$ values for the two methods of exposure was not significant. However histopathological examination revealed differences in the nature and distribution of pathologic changes observed in animals exposed by the two routes of administration. Animals exposed by inhalation died as a result of ulcerative laryngitis and laryngeal edema with only minimal pulmonary pathologic alterations. Animals exposed by lavage, where the larynx was not exposed to Triton X-100, died from pulmonary edema and acute exudative pneumonia, these results demonstrate the need for careful selection of exposure methods to meet the specific objectives of a toxicology study.     

Uptake,distribution, and effects of carbon tetrachloride in rainbow trout (Salmo gairdneri)

Uptake, distribution, and effects of CCl₄ were studied in rainbow trout. Carbon tetrachloride (1 ml/kg, ip) produced 5- to 10-fold increases in serum GOT, GPT, and ICD activities, whereas exposure of trout to CCl₄ in the tank water (1–80 mg/liter) produced neither mortality nor significant changes in enzyme activities. CCl₄ residue(s) appeared highest in concentration in the adipose tissue, followed by liver, brain, and spleen, and was lowest in gill regardless of the administration route. The elimination rates of ¹⁴C residue(s) from the tissue samples were most rapid in muscle ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{β = 1.7}\text{hr}$) and relatively prolonged for liver ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{β = 38.9}\text{hr}$). Maximum liver concentrations of ¹⁴C residue(s) were reached at 2 hr by either ip (1 ml/kg) or water exposure (80 mg/liter) and were 4.8 μmol/g and 0.75 μmol/g, respectively. No increase in liver triglyceride (TG) concentrations were noted at liver CCl₄ concentrations that have been associated with increased TG levels in the rat. Histological examination of tissues revealed varying degrees of liver and splenic necrosis 6 hr after administration of CCl₄.     

Biological activity of technical Aroclor 1254 compared to Aroclor 1254 residues: Swine fat residues fed to boiler cockerels

Fat from Aroclor 1254-treated swine was rendered and incorporated into the diets of broiler chicks for 3–4 weeks. The technical Aroclor 1254 which was fed to the swine was also mixed into control lard for comparison at dietary concentrations of 0.07–9.0 mg/kg. The swine-residue PCB seemed to have a higher proportion of strong microsomal inducers, but the technical PCB was slightly more effective in inducing ethoxy resorufin and $\text{p-}\text{nitroanisole}$ (pNA) $\text{O-}\text{dealkylases}$ than the swine-residue PCB. No overt signs of toxicosis were apparent and one of the diets resulted in changes in growth, relative organ weights, microsomal protein or high affinity pNA $\text{O-}\text{dealkylase}$. Increases in cytochrome(s) $\text{P-450}$ were significant only at the higher dietary concentrations (approx. 9 mg/kg) while ethoxyresorufin $\text{O-}\text{dealkylase}$ was induced at dietary concentrations below 1 mg/kg.     

Assessment of the teratogenic potential of piperonyl butoxide, biphenyl, and phosalone in the rat.

Technical grades of piperonyl butoxide and biphenyl, and a formulation of phosalone containing 30% ($\text{w}\text{w}$) of phosalone, were administered by esophageal intubation to rats on Days 6–15 of gestation. Dams were killed on Day 22 of gestation and fetuses were evaluated by routine teratologic methods. Test doses ranging from 62.5–500 mg/kg for piperonyl butoxide, 12.5–50 mg/kg for the phosalone formulation, and 125–500 mg/kg for biphenyl, elicited neither teratogenicity nor any adverse maternal effects. Biphenyl, at a dose level of 1000 mg/kg, elicited fetal and materal toxicity.     

The blockade of bulbospinal inhibition by imipramine, desipramine and pargyline

Bulbospinal inhibition of the spinal cord monosynaptic reflex was antagonized by im-ipramine HCl (5 $\text{mg}\text{kg}$), desipramine HCl (4.8 $\text{mg}\text{kg}$) and pargyline HCl (30.0 $\text{mg}\text{kg}$) in unanaesthetized, decerebrate cats. The blocking action of imipramine was prevented in animals pretreated for three consecutive days with dl-p-chlorophenylalanine (300 $\text{mg}\text{kg}$) but not in animals pretreated with dl-α-methyl-p-tyrosine methyl ester HCl (125 $\text{mg}\text{kg}$) 16 and 4 hr prior to recording. These results do not support the proposal of Clineschmidt and Anderson (1970) that the bulbospinal inhibitory pathway contains a 5-hydroxytryptamine (5-HT) link. Rather, the findings suggest that 5-HT is involved in antagonizing bulbospinal inhibition of the monosynaptic reflex.     

Mercuric chloride stress on serum transaminase activity in Notopterus notopterus

Mercuric intoxication at sublethal levels ($\text{1}\text{5}$, $\text{1}\text{10}$, $\text{1}\text{15}$, $\text{1}\text{20}$ or $\text{1}\text{25}$ fractions of 96 h LC₅₀) produced alterations in the activity of serum glutamic oxalacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) of Notopterus notopterus. The difference between control and treated fish was found to be significant at P < 0.05, P < 0.01 and P < 0.001 levels. Maximum (81.75%) significant (P < 0.001) effect was observed in SGOT: maximum (69.23%) significant (P < 0.001) effect was observed in SGPT in fish exposed for 60 days.     

Reproduction studies with 1α,25-dihydroxyvitamin D3 (calcitriol) in rats and rabbits

Reproduction and teratology studies were performed in rats and rabbits with 1α,25-dihydroxyvitamin D₃ (calcitriol). Dosages of 0.02, 0.08, and 0.3 μg/kg/day were administered orally as a solution in Neobee oil. In rat teratology studies, no substantial differences were noted between control animals and animals treated with calcitriol from Days 7 through 15 of gestation with respect to litter sizes, resorption rates, pup weights, or external, visceral, and skeletal abnormalities. No adverse effects on either fertility or neonatal development were noted in rat reproduction studies in which male and female rats were pretreated prior to mating through sacrifice on Day 13 of gestation or through lactation Day 21. No adverse effect on perinatal development was noted in litters from females treated from Day 15 of gestation through Day 21 of lactation. However, hypercalcemia and hypophosphatemia were observed in treated pregnant female rats at dosages of 0.08 and 0.3 μg/kg/day and increased serum urea nitrogen was observed at 0.3 μg/kg/day. Hypercalcemia calcemia was noted in pups from dams receiving 0.08 and 0.3 μg/kg/day calcitriol. There was no decrease in the percentage bone ash as determined on lactation Day 21 in either treated females or their pups as compared to controls. In rabbits treated from Days 7 through 18 of gestation with 0.3 μg/kg/day, $\text{3}\text{16}$ rabbits died. Other signs of toxicity included maternal weight loss, an increased resorption rate and neonatal mortality. Two litters at 0.3 μg/kg/day and 1 litter at 0.08 μg/kg/day contained fetuses with multiple abnormalities. These studies demonstrated that in pregnant animals the observed effects of calcitriol are characteristic of those reported for vitamin D₃. In rabbits, dosages of 0.3 μg/kg/day calcitriol produced maternal and fetotoxic effects.     

The synergistic effect of reduced visual input on ketamine action: the possible role of the pineal gland

Studies were performed in cats with eyes open or eyes covered prior to the administration of 20–30 mg/kg of ketamine i.p. The animals were divided into the following groups: intact; cervical sympathectomized; pinealectomized; and sham pinealectomized. In the intact group 20 mg/kg of ketamine induced ataxia and hallucinoid behavior whereas the 25 mg/kg dose of ketamine induced a cataleptoid state. When lenses were placed on the eyes for 1 hr 20 mg/kg of ketamine induced an augmentation of the ketamine effect, e.g. cataleptoid behavior similar to that noted following 25 mg/kg ketamine. When the eyes were covered for one hour and then the lenses removed and the eyes remained uncovered for $\text{1}\text{2}$ hr prior to receiving 20 mg/kg of ketamine, no augmentation was observed whereas administration of drug at the same time that the lenses were removed induced the augmented response. Cervical sympathectomy and pinealectomy failed to demonstrate the augmentation effect when the eyes were covered. Sham pinealectomized animals responded in the same manner as the intact controls. Implied in these findings is the concept that changes in visual input to the pineal gland appears to influence the effect of a 20 mg/kg dose of ketamine such that reduced input augments the ketamine effect to an equivalent of 25 mg/kg of ketamine.     

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.     

Effects of apomorphine on self-stimulation

In rats, self-stimulation (SS) from posterior lateral hypothalamus and ventromedial tegmentum was suppressed by the ip administration of alpha-methyl-para-tyrosine methyl ester (α-MPT, 100 mg/kg). Apomorphine (0.25 or 0.5 mg/kg) was injected ip $\text{3}\text{1}\text{2}\text{hr}$ after α-MPT treatment. Self-stimulation was reinstated to a significant degree, after 2 hr for the 0.25 mg/kg group, and 3 hr for the 0.5 mg/kg group. Apomorphine given after saline control, elicited an immediate suppression of SS for approximately $\text{1}\text{2}\text{hr}$ in the case of 0.25 mg/kg and $\text{1}\text{1}\text{2}\text{hr}$ for 0.5 mg/kg.     

Effect of administrative vehicle on oral 1,1-dichloroethylene toxicity

The relationship between the acute toxicity and biologic fate of 1,1-dichloroethylene (1,1-DCE) was examined in fasted and fed male Sprague-Dawley rats given 200 mg 1,1-DCE/kg orally in a mineral oil, a corn oil, or an aqueous Tween-80 vehicle. Exhalation of unchanged 1,1-DCE by individual rats was monitored at selected 15-min intervals for 5 hr and all rats were sacrificed at 6 hr. The administrative vehicle affected the magnitude of liver injury in fasted rats; with mineral oil or corn oil, injury was massive [> 100-fold elevation of glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT)] whereas with the aqueous Tween-80 vehicle, injury was moderate t 15-fold elevation of GOT and GPT). In contrast, in all fed groups liver injury was slight (two- to threefold elevation of GOT and GPT). Rats with massive liver injury also had an ～50-fold increase in plasma free hemoglobin and their kidneys exhibited numerous granular “heme” casts in Henle's loop without apparent degenerative changes in either glomeruli or tubular epithelium. No pathologic changes were observed in heart, lungs, spleen, adrenals, or duodenum. The administrative vehicle did not affect the total amount of 1,1-DCE exhaled, which was approximately half the given dose, nor did the vehicle affect the initial rapid phase of 1,1-DCE exhalation, which lasted ～1 hr and had $\text{t}\text{1}\text{2}$ values ranging from 15 to 21 min for the fasted groups and from 10 to 13 min for the fed groups. In contrast, the later slow phase of 1,1-DCE exhalation was predictably affected by the administrative vehicle; $\text{t}\text{1}\text{2}$ values for the fasted and fed groups, respectively, were most prolonged with the poorly absorbed mineral oil vehicle (257 and 280 min), intermediate with the more digestable corn oil vehicle (73 and 103 min), and briefest with the more absorbable aqueous Tween vehicle (22 and 42 min). Further studies are needed to determine if the relative resistance of the fed animals to hepatic injury is due to the capacity of these animals to detoxify 1,1-DCE for a longer duration than the fasted animals.     

Participation of superoxide anions at the prostaglandin phase of carrageenan foot-oedema.

Bovine Superoxide dismutase (SOD: 0.5–2.0 mg/kg) administered intravenously to rats, completely suppressed the prostaglandin phase swelling (2–4 hr) of carrageenan foot-oedema, but had no effect on the histamine and serotonin phase ($\text{1}\text{2}\text{–1}\text{1}\text{2}\text{hrs}$.). Heat-inactivated SOD, bovine serum albumin and catalase and high doses of the hydroxyl radical scavengers, sodium benzoate and d-mannitol or the oxygen scavenger, 1.3-diphenylisobenzofuran had no effect on the swelling. Mepylamine plus methysergide did not influence the inhibitory action of SOD. Carrageenan foot-oedema of agranulocyte rats, induced by methotrexate injections, was more susceptible than that of normal rats to SOD inhibition. Even at 1 hr, about 70 per cent inhibition of swelling was observed suggesting the importance of macrophages in this inflammation model. Indomethacin and oxyphenbutazone were also examined for comparison with the effect of SOD. The role of Superoxide anions in inflammation is discussed in connection with macrophage emigration, releases of lysosomal enzymes and prostaglandin biosynthesis.     

Delays in the postnatal increase of cerebral cytochrome concentrations in lead-exposed rats.

Increases in the cytochrome content of the developing rat cerebral cortex were observed spectrally, directly in the tissue using dual-wavelength spectroscopy. It was found that the contribution of hemoglobin entrapped in the tissue contributed significantly to the spectra. However, this interference was equivalent with varying age and could be treated as a constant. Between 10 and 24 days of age, a 4–5-fold increase in absorbance could be attributed to peaks of the cytochrome intermediates.Administration of lead (Pb) (5–200 mg $\text{Pb}\text{1}$) to female rats, from 14 days prior to breeding through weaning of pups, resulted in a delay in the normal increase in the cytochrome of the cerebral cortex of male offspring. Calculated on the basis of rates of cytochrome accumulation, the effect of Pb was most marked between 10 and 15 days after birth. At 30 days of age, Pb-treated animals recovered the cytochrome content displayed by control animals. These data indicate a delay in the biochemical development of rat brain at very modest elevations of blood Pb concentrations relative to that encountered in human populations.     

Effects of 3-methylcholanthrene on covalent binding and toxicity of 4-ipomeanol in inducible and non-inducible (B6D2) mice

The effects of 3-methylchloanthrene (MC) on the covalent binding and toxicity of 4-ipomeanol (1-(3-furyl)-4-hydroxypentanone, IPO) were studied in $\text{(}\text{C}\text{57}\text{BL}\text{6}\text{N}\text{(}\text{DBA}\text{2}\text{N}\text{)}\text{F}{}_1\text{×}\text{DBA}\text{2}\text{N}$ backcross (B6D2)D2) mice previously segregated into relatively “inducible” or “non-inducible” groups based on zoxazolamine (2-amino-5-chlorobenzoxazole, ZOX) paralysis times following MC treatment. MC decreased the covalently bound IPO metabolite(s) both in the lungs and in the kidneys of “inducible” and “non-inducible” mice when compared to controls not pretreated with MC. On the other hand, concentrations of covalently bound IPO metabolite(s) in liver were increased in “inducible” mice and decreased in “non-inducible” mice by MC pretreatment when compared to non-pretreated heterogenous mice. Associated with MC pretreatment was a significant decrease in the acute lethality of IPO both in the “inducible” and in the “non-inducible” mice when compared to non-pretreated control animals (LD₅₀: 213 ± 2, 140 ± 14 and 14 ± 4 mg/kg, respectively). Hepatic necrosis occurred frequently in the “inducible” mice and occasionally in the “non-inducible” mice given large IPO doses near the respective LD₅₀-values. Hepatic necrosis was never observed in non-pretreated mice receiving near lethal doses of IPO. These results support previous studies indicating that reactive IPO metabolites binding to extrahepatic tissues are formed in situ and do not reflect binding of blood-borne metabolites formed in the liver.     

Factors regulating drug cue sensitivity: Limits of discriminability and the role of a progressively decreasing training dose in cocaine-saline discrimination

This study determined the limits of discriminability of cocaine HCl and the role of the training dose of cocaine in cocaine-saline discrimination. Rats were trained to discriminate 10 mg/kg of cocaine HCl from saline in a two-lever operant procedure, and then were retrained on progressively smaller doses of the training drug. Stimulus generalization experiments with test doses of cocaine $\text{1}\text{2}$ to $\text{1}\text{250}$ times the training dose, were carried out each time the animals had reached criterion on successive training doses. It was found that the smallest training dose of cocaine HCl at which rats can reach criterion ranges from 0.31 to 2.5 mg/kg, the median being 0.66 mg/kg. As had been demonstrated earlier with fentanyl, the effects of the training dose on the generalization gradient for cocaine could be related to the relative discriminability of that dose. It is also suggested, however, that other effects of cocaine add to the general effects of the training dose in determining the slope of the gradient and the ED₅₀ of the training drug. The 2.5 mg/kg training dose of cocaine may perhaps yield better pharmacological specificity than any other dose in the 0.16–10 mg/kg range examined here; at this training dose, the gradient's slope is steepest and the ratio of training dose to ED₅₀ is minimal. Also, the potency difference between apomorphine and cocaine in generalizing with the cocaine training dose was 17-fold at 2.5 mg/kg, but only 3-fold at the 10 mg/kg training dose of cocaine. The data are consistent with the conclusion that the training dose has important effects on the stimulus generalizations that may occur following drug-saline discrimination training. However, a comparison between cocaine and fentanyl revealed that these effects were not simply identical across different training drugs.     

Excretion of cadmium and mercury in rat saliva

The excretion of cadmium and mercury in saliva was studied in urethane-anesthetized male rats given single intravenous injections of ¹⁰⁹CdCl₂ or ²⁰³HgCl₂ (0.1 or 1.0 mg divalent cation/kg). Pilocarpine (20 mg/kg, ip) was used to stimulate salivation. All doses produced a distinct and persistent increase in blood pressure (15–25 mm Hg), an increase in salivary flow rate and an increase (19–26%) in salivary gland weight. Metal levels in saliva (S) and submaxillary gland tissue (T), relative to blood (B), plasma (P), and filtrate (F) were determined. Cadmium and mercury were detected in S and T at both doses. The following relative order was apparent: $\text{S}\text{F}\text{>}\text{S}\text{P}\text{>-}\text{S}\text{B}$. $\text{S}\text{F}$ ratios were >1, suggesting a concentrating effect by the salivary gland. $\text{S}\text{B}$ and $\text{S}\text{P}$ ratios for mercury increased with increasing dose; $\text{S}\text{B}$ and $\text{S}\text{P}$ ratios for cadmium decreased with increasing dose. Similar dose-related effects were apparent in the $\text{T}\text{B}$ and $\text{T}\text{P}$ ratios.