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R H McKee

Publications and source records attributed to R H McKee.

At least 19 recordsLinked to original sources
PubMed2006

Model studies for evaluating the acute neurobehavioral effects of complex hydrocarbon solvents I. Validation of methods with ethanol.

As a preliminary step to evaluating the acute neurobehavioral effects of hydrocarbon solvents and to establish a working model for extrapolating animal test data to humans, joint neurobehavioral/toxicokinetic studies were conducted which involved administering ethanol to rats and volunteers. The specific objectives of the present studies were to evaluate the acute central nervous system (CNS) effects of ethanol in rats and humans and to assess relationships between internal levels of exposure and behavioral effects. A more general objective was to validate a battery of neurobehavioral tests that could be used to carry out comparative studies in both species. Accordingly, a range of tests including standardized observational measures, spontaneous motor activity assessments and learned visual discrimination performance was utilized in rat studies to evaluate acute CNS effects. Groups of rats were given ethanol at levels of approximately 0.5, 1.0 or 2.0g/kg, with blood level measurements to verify internal doses. In a volunteer study, 12 healthy male subjects were given 0.65g/kg ethanol, a level approximating the limit for motor vehicle operation in The Netherlands, and neurobehavioral effects were measured prior to and 1 and 3h after ethanol administration, with a computerized neurobehavioral test battery. Blood and air measurements were made to quantify internal doses. Results of the behavioral tests in rats provided evidence of ethanol-induced changes in neuromuscular, sensori-motor, and activity domains. There were also significant changes in visual discrimination, particularly in the areas of general measures of responding and psychomotor speed. In humans there were small but statistically significant effects on learning and memory, psychomotor skills and attention. However, the effects were subtle and not all parameters within given domains were affected. These studies demonstrated a qualitative similarity in response between rats and humans.

Adult↗
PubMed2002

Tumor induction in mouse liver: di-isononyl phthalate acts via peroxisome proliferation.

Recently several chronic toxicity/carcinogenicity studies of di-isononyl phthalate (DINP) have been reported. These studies defined effect levels for liver tumors in male and female F344 rats at dietary levels exceeding 700 mg/kg/day; the no effect levels were 359 mg/kg/day in males and 442 mg/kg/day in females. Similar results were found in male B6C3F1 mice, but in female mice a significant increase in liver tumors was found at 336 mg/kg/day, making 112 mg/kg/day the NOAEL for liver tumors in that sex and species. DINP induces peroxisomal proliferation, and that, along with evidence that DINP is not mutagenic, is presumptive evidence for peroxisomal proliferation as the underlying mode of action for liver tumor development. To further explore the relationship between peroxisome proliferation and tumor induction in male and female mice, indicators of peroxisomal proliferation including liver weight, peroxisomal volume density, induction of peroxisomal enzyme activity, enhanced replicative DNA synthesis, and rates of apoptosis were measured at all of the dietary levels used in the chronic study in mice (500, 1500, 4000, and 8000 ppm, or approximately 100, 300, 800, and 1600 mg/kg/day). Liver weights, peroxisomal volume, and peroxisomal enzyme activity were significantly elevated in both male and female mice at the tumorigenic levels. Cell proliferation was also elevated in male and female mice, although the increases at levels below 4000 ppm in female mice were not significantly different from control values. Apoptosis was elevated at the 4000 and 8000 ppm levels, paralleling the increases in liver weight. These data along with previous results satisfy the criteria of the International Agency for Research on Cancer (IARC) and demonstrate that peroxisomal proliferation was indeed the mode of action for DINP-induced liver tumor induction in mice.

Administration, Oral↗
PubMed2001

Reversibility and persistence of di-2-ethylhexyl phthalate (DEHP)- and phenobarbital-induced hepatocellular changes in rodents.

The tumor promotion stage of chemical carcinogenesis has been shown to exhibit a persistence of cellular effects during treatment and the reversibility of these changes upon cessation of treatment. Inhibition of gap-junctional intercellular communication and increased replicative DNA synthesis appear to be important in this process. The present study assessed the persistence and reversibility of gap-junctional intercellular communication inhibition, peroxisomal proliferation, and replicative DNA synthesis in livers from male F344 rats and B6C3F1 mice. Dietary administration of 20,000 mg/kg DEHP to male rats for 2 weeks decreased intercellular communication (67% of control) and enhanced replicative DNA synthesis (4.8-fold over control). Elevation of the relative liver weight and the induction of peroxisomal beta oxidation were also observed following treatment with 20,000 mg/Kg DEHP for 2 weeks. Following DEHP administration at a dose of 6000 mg/kg for 18 months, inhibition of gap-junctional intercellular communication persisted, and the relative liver weight and induction of peroxisomal beta oxidation remained elevated in both rats and male B6C3F1 mice. Treatment of rats and mice with phenobarbital for 18 months (500-mg/kg diet) also produced an increase in relative liver weight and a decrease in cell-to-cell communication. In recovery studies in which DEHP was administered to male F344 rats for 2 weeks and then withdrawn, the relative liver weight, rate of peroxisomal beta oxidation, increase in replicative DNA synthesis, and inhibition of gap-junctional intercellular communication returned to control values within 2 to 4 weeks after DEHP treatment ceased. Recovery studies with phenobarbital produced similar results. The primary active metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP), was detected in the livers of animals treated with DEHP for greater than 2 weeks. However, it could not be detected after removal of DEHP from the diet for 2 weeks. This study demonstrated that inhibition of gap-junctional intercellular communication, along with indicators of peroxisomal proliferation, including increased relative liver weight and enhanced peroxisomal beta oxidation, persist while DEHP treatment continues but reverses when treatment is stopped. Studies with phenobarbital produced a similar pattern of response.

Animals↗
PubMed2000

The role of inhibition of gap junctional intercellular communication in rodent liver tumor induction by phthalates: review of data on selected phthalates and the potential relevance to man.

Inhibition of gap junctional intercellular communication (GJIC) has been postulated as a nongenotoxic carcinogenic mechanism, probably related to tumor promotion. Recent studies assessed the role of GJIC in the induction of rodent liver tumors by high levels of phthalate esters. Studies with di(2-ethylhexyl) (DEHP) and diisononyl (DINP) phthalates demonstrated that inhibition of GJIC in rats and mice was well correlated with induction of both liver tumors and markers for peroxisomal proliferation. However, GJIC was unaffected in hamsters and primates, species in which phthalate treatment does not induce peroxisomal proliferation. In vitro studies which extended the database to include human liver cells mirrored the in vivo situation; GJIC was inhibited in rat and mouse cells but not in cells from unresponsive species including humans. Peroxisomal proliferation has been characterized as a species-specific process essential for phthalate-induced rodent liver tumor induction. That GJIC was not inhibited in primate liver or human liver cells provides evidence for a second species-specific carcinogenic process. Thus the GJIC data along with those from studies of peroxisomal proliferation support the view that the carcinogenic effects of DEHP and DINP in rodents are not relevant to humans.

Animals↗
PubMed1999

Assessment of the utility of the micronucleus test for petroleum-derived materials.

The micronucleus test is a commonly used in vivo assay for chromosomal damage and is an integral part of many mutagenicity testing strategies. The present report describes an assessment of the micronucleus test for the detection of mutagenic potential of petroleum-derived materials. To this end, studies were conducted with catalytically cracked clarified oil (CCCO). This material contains high levels of polycyclic aromatic constituents (PAC) and is a very potent inducer of mouse skin tumors. CCCO is also active in the Salmonella assay and other in vitro tests. As CCCO is the most potent of the various petroleum-derived materials in other assays, it was assumed to be the most easily detectable in the micronucleus test. CCCO was tested in standard mouse micronucleus tests utilizing oral and intraperitoneal injection for test material administration. All of these studies were negative, although DMBA, tested at roughly equivalent levels based on potency in the Salmonella assay, produced statistically significant increases in micronucleus frequency. In a second series of studies, aromatic fractions of CCCO were prepared and tested at up to acutely toxic levels. Results of these studies were also negative. Finally, another petroleum-derived material which is carcinogenic and contained PAC was tested in the micronucleus assay. It also produced negative results. Thus, it was concluded that petroleum-derived materials do not produce clastogenic effects in vivo in the mouse micronucleus test, despite the fact that some pure polycyclic aromatic hydrocarbons are quite active in this assay.

Animals↗
PubMed1999

The role of dermal irritation in the skin tumor promoting activity of petroleum middle distillates.

Petroleum middle distillates (PMDs), a class of hydrocarbons which boil between 350-700 degrees F, are tumor promoters in mouse skin. The promotional activity is produced under conditions that also result in local changes, including chronic irritation and epidermal hyperplasia. The present study was conducted by comparing equal weekly doses of irritating and minimally or nonirritating test materials, to assess whether tumor promotion was a secondary response to these effects. Four PMDs, C10-C14 normal paraffins (NP), lightly refined paraffinic oil (LRPO), Jet Fuel A (JF), and steam-cracked gas oil (SCGO), were evaluated. Test materials were applied undiluted (2x/week) or as 28.6% (7x/week) or 50% (4x/week) concentrations in mineral oil for 52 weeks following initiation with dimethylbenzanthracene (DMBA). When applied undiluted, all materials produced moderate irritation and significant increase in tumor incidence. When NP, LRPO, or JF were applied in mineral oil diluent, skin irritation was generally ameliorated and few, if any, tumors were produced. SCGO was irritating and produced a significant increase in tumor frequency when administered in mineral-oil diluent. These data indicate that the promotional activity of straight-run PMDs is likely related to chronic irritation at the application site and not to dose. Thus, when used appropriately in the absence of prolonged irritation, these materials should not present a tumorigenic hazard to humans.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1999

Retrospective evaluation of alpha 2u-globulin accumulation in male rat kidneys following high doses of diisononyl phthalate.

Diisononyl phthalate (DINP), a widely used plasticizer, has been evaluated in two chronic studies in rats and one in mice. In the early 1980s, Exxon found no carcinogenic potential at the estimated maximum tolerated dose (MTD) of 0.6% (307 mg/kg/ day for male rats) administered in the diet of rats for 2 years. A recent study conducted at dietary levels up to 1.2% DINP (733 mg/kg/d for male rats) reported kidney tumors in male rats at the high treatment level, but not in female rats nor mice of either sex. Because these tumors occurred only in male rats, and only at high doses, the male rat-specific alpha 2u-globulin (alpha2UG) mechanism of action was investigated. Technological advances in immunohistochemical staining and computerized image analysis techniques permitted measuring the accumulation of alpha2UG in archived kidneys from the earlier Exxon study. Using archived tissue obtained at the 12-month interim sacrifice, we identified a dose-dependent accumulation of alpha2UG in specific regions of male rat kidneys only. An increase in cell proliferation was confirmed by immunohistochemical detection of proliferating-cell nuclear antigen (PCNA) and was confined to the areas of alpha2UG accumulation. H and E-stained sections revealed tubular epithelial hypertrophy and regeneration, consistent with the immunohistopathology findings. These findings are consistent with the alpha2UG mechanism of tumorigenesis, which is not regarded as relevant for humans. Thus, exposure to DINP produced a dose-dependent alpha2UG accumulation in male rat kidneys, significant at a dietary level of 0.6% and a likely mechanism for the kidney tumors seen only in male rats administered higher dietary levels of DINP.

Alpha-Globulins↗
PubMed1998

A comprehensive evaluation of the mechanism of skin tumorigenesis by straight-run and cracked petroleum middle distillates.

The role of skin irritation and other factors on the tumorigenic activity of petroleum middle distillates (PMDs) in mice was examined in a comprehensive research program. The program culminated in a 2-year dermal carcinogenicity study which compared the effects of equal weekly doses of irritating and nonirritating PMDs. Modified Ames mutagenicity studies and three- to seven-ring polycyclic aromatic compound (PAC) analyses indicated that the mutagenic activity of PMDs was correlated to PAC content. In subchronic and subacute studies, PMDs produced marked skin irritation which was ameliorated if the test samples were diluted in mineral oil. The reduction in irritation level was not a result of reduced dermal absorption. Straight-run kerosine (SRK), straight-run gas oil (SRGO), and catalytically cracked light cycle oil (LCO) were evaluated in the dermal carcinogenicity study. Test materials were applied either undiluted (2x/week) or as 28.5% (7x/week) or 50% (4x/week) concentrations in mineral oil for a total weekly dose of 100 microliters PMD per animal. All three materials produced moderate to marked skin irritation and increased tumor frequency when applied undiluted. When diluted, the irritant effects of SRK and SRGO, which contain low levels of PACs, were ameliorated, and there were no significant increases in tumors relative to controls. LCO, containing 8.7% three- to seven-ring PACs, increased tumor frequency when diluted, even when skin irritation was limited. These data indicate that the tumorigenic activity of straight-run MDs is likely a consequence of a nongenotoxic process, associated with frequent cell damage and repair. PMDs which contain low levels of three- to seven-ring PACs are unlikely to cause tumors in the absence of prolonged skin irritation. In addition, genotoxic mechanisms may also contribute to tumor formation for other PMDs containing higher levels of PACs, e.g., products blended with cracked stocks.

Animals↗
PubMed1997

Assessment of the in vivo mutagenic potential of methyl tertiary-butyl ether.

Methyl tertiary-butyl ether (MTBE) is one of the highest production volume chemicals in the USA. Previous results from in vitro genetic toxicity studies suggested that it was not mutagenic. However, chronic exposure at high levels resulted in liver tumors in female mice and kidney tumors in male rats. The current program assessed in vivo genotoxicity and also explored the possibility that a mutagenic mechanism was involved in the carcinogenic process. The specific tests used included the Drosophila sex-linked-recessive-lethal test, the rat bone marrow cytogenetics test, the mouse bone marrow micronucleus test and the in vivo-in vitro hepatocyte unscheduled DNA synthesis test in the mouse. All tests produced negative results, indicating that the potential for in vivo mutagenic activity was low. These data also suggest that the tumorigenic activity was probably the result of a non-genotoxic process.

Air Pollutants↗
PubMed1994

Evaluation of the genetic toxicity of middle distillate fuels.

Petroleum middle distillate (PMD) fuels are mixtures of hydrocarbons that distill between approximately 170-370 degrees C. Commercial products that fall into this category include kerosine, diesel fuel, jet fuel, and home heating oil. These products contain both saturated (paraffins and cycloparaffins) and aromatic species, but because of the boiling range normally contain very small amounts of the 3-6 ring polycyclic aromatic hydrocarbon (PAH) constituents, which are considered to be carcinogenic. Nevertheless, there is evidence of weak tumorigenic activity when these materials are repeatedly applied to mouse skin. In the current studies representative products were tested in two commonly used, short-term assays for genetic toxicity, the Salmonella/mammalian microsome mutagenicity assay and the mouse bone marrow micronucleus test. All samples were inactive in the micronucleus assay, and three were clearly inactive in the Salmonella test. Of the remaining two, one was marginally active in the Salmonella assay, and one was equivocal. The marginally active sample contained detectable levels of PAH due to the use of catalytically cracked materials as blending stocks. The results indicated that PMDs that do not contain cracked material were not mutagenic. Thus they may produce tumors via nongenotoxic processes. Those products that do contain cracked stocks may have sufficient PAH to be mutagenic in the Salmonella assay, and in those cases the PAH might also contribute to tumor formation.

Analysis of Variance↗
PubMed1994

Developmental toxicity evaluation of isopropanol by gavage in rats and rabbits.

Timed-pregnant CD (Sprague-Dawley) rats, 25/group, were dosed orally with aqueous isopropanol (IPA; CAS No. 67-63-0) solutions at 0, 400, 800, or 1200 mg/kg/day, once daily on Gestational Days (GD) 6 through 15 at a dosing volume of 5 ml/kg. Artificially inseminated New Zealand white rabbits, 15/group, were dosed orally with IPA at 0, 120, 240, or 480 mg/kg/day once daily on GD 6 through 18 at 2 ml/kg. Maternal body weights, clinical observations, and food consumption were recorded throughout gestation for both species. At scheduled euthanization for both species (GD 20, rats; GD 30, rabbits), fetuses were weighed, sexed, and examined for external, visceral (including craniofacial) and skeletal alterations. For both species, the pregnancy rate was high and equivalent across all groups; no dams or does aborted, delivered early, or were removed from study. In rats, two dams (8%) died at 1200 mg/kg/day and one dam (4%) died at 800 mg/kg/day. Maternal body weights and weight gain were equivalent across all groups, except for statistically significantly reduced gestational weight gain (GD 0-20; 89.9% of control value), associated with statistically significantly reduced gravid uterine weight at 1200 mg/kg/day (89.2% of control value). There were no treatment-related clinical signs or effects on maternal food consumption. All gestational parameters evaluated were equivalent across groups, including pre- and postimplantation loss, fetal sex ratios, and litter size. Twenty-two to 25 litters were examined per group. Fetal body weights per litter were statistically significantly reduced at the two highest doses (97.3 (n.s.), 94.7, and 94.3% of controls at 800 mg/kg/day and 92.1, 91.9, and 95.4% of controls at 1200 mg/kg/day for all fetuses and males and females separately). No evidence of increased teratogenicity was observed at any dose tested in rats. In rabbits, four does (26.7%) died at 480 mg/kg/day. Maternal body weights were statistically significantly reduced during treatment (GD 6-18) at 480 mg/kg/day (45.4% of control value) with a nonsignificant reduction in gestational weight change (GD 0-30; 77.3% of control value) at this dose. Profound clinical signs of toxicity and statistically significantly reduced maternal food consumption were observed at 480 mg/kg/day. All gestational parameters were equivalent across all doses administered. Thirteen to 15 litters were evaluated per group except for the 480 mg/kg/day group with 11 litters (due to maternal deaths). There were no treatment-related effects on pre- or postimplantation loss, fetal sex ratio, litter size, or fetal body weight/litter. Moreover, no evidence was found of increased teratogenicity at any dose tested in rabbits. Therefore, IPA was not teratogenic to CD rats or to NZW rabbits. The NOAELS for both maternal and developmental toxicity were 400 mg/kg/day in rats, and were 240 and 480 mg/kg/day, respectively, in rabbits.

1-Propanol↗
PubMed1994

Developmental neurotoxicity evaluation of orally administered isopropanol in rats.

Isopropanol was administered by gavage to timed-mated rats from Gestation Day (GD) 6 through Postnatal Day (PND) 21. Doses administered were 0, 200, 700, or 1200 mg/kg/day in a volume of 5 ml/kg. The dams were allowed to deliver and body weights and food consumption were recorded during gestation and lactation. Pups were counted, examined, sexed, and weighed on PND 0, 4, 7, 13, 17, 21, 36, 49, and 68. Litters were culled to eight pups (4:4 or 5:3 sex ratio) on PND 4 and litters without acceptable numbers of male and female pups were eliminated from the study. Pups were weaned on PND 22, and two pups from each litter and their dams were killed. Six of these pups from each dose group were perfused in situ for histopathological examination of the central and peripheral nervous system. Brains of the remaining pups were divided into four regions and weighed. Maternal liver and kidney weights were recorded. Weaned pups were assessed for day of testes descent or vaginal opening and for motor activity on PNDs 13, 17, 21, 47, and 58; auditory startle on PNDs 22 and 60; and active avoidance on PNDs 60-64. These pups were euthanized and examined on PND 68. One high-dose dam died on PND 15, but there were no other clinical observations or effects on maternal weight, food consumption, or gestation length. Pup survival, weight, sex ratio, and sexual maturation were unaffected. There were no biologically significant findings in the behavioral tests, no changes in organ weights, and no pathological findings that could be attributed to isopropanol exposure. In conclusion, there was no evidence of developmental neurotoxicity associated with isopropanol exposure as high as 1200 mg/kg/day.

1-Propanol↗
PubMed1994

Increased frequency of resistance to terminal differentiation in C3H mouse cells produced by genotoxic but not nongenotoxic carcinogens.

Certain cells present in mouse skin are resistant to calcium-induced terminal differentiation. It is believed that these calcium-resistant cells (CRCs) represent an early stage in the carcinogenic process, in part, because frequency increases after treatment with mutagens. The frequency of CRCs in C3H mouse skin was measured before and after treatment with certain petroleum-derived materials. One objective was to determine whether this assay could differentiate between genotoxic and nongenotoxic mouse skin carcinogens. An additional objective was to determine whether CRCs are an important factor in the tumorigenicity of petroleum middle distillates (PMDs), a class of apparently nongenotoxic mateials. Three petroleum-derived materials were tested: mineral oil (MO), a noncarcinogenic product used as the negative control; catalytically cracked clarified oil (CCCO), a highly carcinogenic and mutagenic material; and a lightly paraffinic (LRPO), a PMD which has produced tumors when repeatedly applied, but is not mutagenic and does not initiate most skin tumors. The CRC frequency was not increased by LRPO treatment; however, a statistically significant and dose-related increase was produced by CCCO. These results are consistent with observations that genotoxic, petroleum-derived liquids are capable of tumor initiation in mouse skin, whereas PMDs which are not genotoxic do not initiate skin tumors. The number of CRCs in untreated and MO-treated mice was approximately twice the tumor frequency measured in bioassays of PMDs. Thus, tumor production associated with these products could be due to promotion of preexisting, spontaneously initiated cells.

Animals↗
PubMed1994

Disposition and pharmacokinetics of isopropanol in F-344 rats and B6C3F1 mice.

The absorption, metabolism, disposition, and excretion of isopropanol (IPA) were studied in male and female rats and mice. Animals were exposed by i.v. (300 mg/kg) and inhalation (500 and 5000 ppm for 6 hr) routes; additionally, IPA was given by gavage to rats only in single and multiple 300 and 3000 mg/kg doses. In the rat approximately 81-89% of the administered dose was exhaled (as acetone, CO2, and unmetabolized IPA); approximately 76% of the dose in mice was exhaled after i.v. bolus but 92% was exhaled following inhalation. Approximately 3-8% of the administered dose was excreted in urine as IPA, acetone, and a metabolite tentatively identified as isopropyl glucuronic acid. Small amounts of radiolabel were found in feces and in the carcass. There were no major differences in the rates or routes of excretion observed either between sexes or between routes of administration. Additionally, repeated exposure had no effect on excretion. However, both the route of administration and the exposure or dose level influenced the form in which material was exhaled. Following exposure to 5000 ppm, a greater percentage of unmetabolized IPA was recovered in the expired air than following exposure to 500 ppm, implying saturation of metabolism.

1-Propanol↗
PubMed1994

Isopropanol 13-week vapor inhalation study in rats and mice with neurotoxicity evaluation in rats.

This study was conducted to evaluate the possible subchronic toxicity as well as neurobehavioral effects of isopropanol, a widely used industrial and commercial solvent. Five groups, each containing 10 Fischer 344 rats/sex and 10 CD-1 mice/sex, were exposed for 6 hr/day, 5 days/week, for 13 weeks to isopropanol vapor at concentrations of 0 (control), 100, 500, 1500, or 5000 ppm. An additional 15 rats/sex were assigned to the 0, 500, 1500, and 5000 ppm groups for assessment of neurobehavioral function. No exposure-related mortalities occurred during the study. The narcotic effects of isopropanol were noted only during exposures at 1500 and 5000 ppm. These signs, noted during exposures, were typically absent following exposures. The only clinical signs observed following exposures included swollen periocular tissue, perinasal encrustation, and ataxia for rats of the 5000 ppm group. Neurobehavioral evaluations indicated no changes in any of the parameters of the functional observational battery; however, increased motor activity for female rats in the 5000 ppm group was noted at Weeks 9 and 13. Decreases in body weight and body weight gain were observed for rats of the 5000 ppm group at the end of the first week of exposure. During the remaining weeks, increases in body weight and/or body weight gain were observed for rats of the 1500 and 5000 ppm groups. No exposure-related effects on body weight were noted for male mice; however, increased body weight and body weight gain were observed for female mice of the 5000 ppm group.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Propanol↗
PubMed1993

Evaluation of the contribution of chronic skin irritation and selected compositional parameters to the tumorigenicity of petroleum middle distillates in mouse skin.

Two-year skin carcinogenicity studies were conducted in C3H mice to assess the effects of irritation and selected compositional parameters on the carcinogenic potential of four petroleum liquids. Three samples (lightly refined paraffinic oil, LRPO; lightly hydrodesulfurized specialty oil, LHSO; jet fuel, JF) can be generically classified as middle distillates, i.e. distillation occurs between 350 and 700 degrees F (175-370 degrees C). The fourth sample was a Steam Cracked Gas Oil (SCGO) that distilled within the same range. In studies that assess the effects of irritation on tumorigenicity, LRPO was tested undiluted or was diluted to 50% and 25% in either mineral oil (which eliminated irritation of the skin) or toluene (which did not). Undiluted LRPO elicited tumors in 8% of the mice. Both dilution procedures eliminated tumorigenic potential. Thus, it was possible to maintain a visible level of skin irritation equivalent to that elicited by undiluted LRPO without inducing tumors. SCGO elicited a chronic irritant state grossly equivalent to LRPO but was not tumorigenic. Jet Fuel A (JF) was tested undiluted using both a standard skin painting protocol and an intermittent dosing schedule in which treatment was suspended periodically to allow skin irritation to resolve. The standard treatment protocol of JF resulted in both marked skin irritation and tumors in 44% of the mice. However, using the intermittent schedule, the tumor yield was reduced to 2%. Collectively these data demonstrate that tumor formation is not a necessary sequelae to chronic skin irritation. Conversely, prevention of a marked chronic irritant state was accompanied by decreased tumor yield. These data suggest that the chronic irritant state may be a necessary but not sufficient condition for tumor formation. In studies to assess the effects of compositional parameters, a lightly hydrodesulfurized specialty oil (LHSO) similar to LRPO but refined to have negligible levels of sulfur compounds (3 ppm), elicited chronic irritant and tumor responses (10%) similar to LRPO. Thus, the level of sulfur compounds does not appear to affect the tumorigenic activity for products in this boiling range. The SCGO which did not produce tumors contained only aromatic hydrocarbons, a finding consistent with previous reports that aromatics may not be the source of tumorigenic potential in petroleum fractions boiling between 350 and 700 degrees F (175-370 degrees C).

Animals↗
PubMed1993

In vitro and in vivo assays of isopropanol for mutagenicity.

To assess the mutagenic potential of isopropanol, an in vitro Chinese hamster ovary (CHO) cell/HGPRT gene mutation assay and a bone marrow micronucleus study in mice were conducted. In the CHO/HGPRT assay, concentration levels ranged from 0.5 to 5.0 mg/ml. No elevated mutant frequencies attributable to treatment were observed in the test under either activated or non-activated conditions. In the micronucleus assay, mice were injected intraperitoneally (IP) with either 350, 1,173, or 2,500 mg/kg of isopropanol at constant volumes of 10 ml/kg. No increased incidence of micronuclei was observed in bone marrow polychromatic erythrocytes (PCEs) harvested at 24, 48, or 72 hr post-dosing. In both assays, negative and positive control mutant frequencies were within historical control ranges. These results, in conjunction with previously published data, clearly demonstrate that isopropanol is not a mutagen.

1-Propanol↗