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J K Baldwin

Publications and source records attributed to J K Baldwin.

At least 19 recordsLinked to original sources
PubMed2000

Inhalation developmental toxicity and reproduction studies with cyclohexane.

The reproductive and developmental toxicity of cyclohexane was assessed in a two-generation reproduction study with Crl:CD BR rats and in developmental toxicity studies with Crl:CD BR rats and Hra:(NZW)SPF rabbits. The animals were exposed whole-body to atmospheric concentrations of 0, 500, 2000, or 7000 ppm cyclohexane. In the two-generation reproduction study, parental effects included statistically significantly lower mean body weight, overall mean body weight gain, and overall mean food efficiency for P1 and F1 females of the 7000 ppm level and statistically significantly lower mean body weight for F1 males of that level. Adult rats exposed to 2000 ppm cyclohexane and above exhibited a transient diminished or absent response to a sound stimulus while in the chambers during exposure. Mean pup weight was statistically significantly lower than control from lactation day 7 throughout the remainder of the 25-day lactation period for both F1 and F2 7000 ppm litters. Changes observed at 500 ppm were either considered not to be compound related or not adverse. Therefore, the systemic-toxicity no-observed-effect level (NOEL) was 500 ppm and the reproductive NOEL was 2000 ppm. The reproductive NOEL was based solely on the decreased pup weights in both the F1 and F2 generations observed at 7000 ppm. In the developmental toxicity studies, only the rats showed evidence of maternal toxicity. For rats in the 7000 ppm group, statistically significant reductions were observed in overall maternal body weight gain and overall maternal food consumption for the treatment period. Rats exposed to 2000 ppm cyclohexane and above again exhibited a transient diminished or absent response to a sound stimulus while in the chambers during exposure. Therefore, for rats, the maternal no-observed-effect level (NOEL) was 500 ppm. In the rabbit developmental toxicity study, no compound-related maternal effects were observed at concentration levels of 7000 ppm and below. Therefore, the maternal NOEL for rabbits was 7000 ppm. No compound-related evidence of developmental toxicity was observed at any test concentration in either species. Therefore, the developmental NOEL for both species was 7000 ppm, the highest concentration tested.

Acoustic Stimulation↗
PubMed1996

Subchronic toxicity of 4-vinylcyclohexene in rats and mice by inhalation exposure.

This study was conducted to evaluate the subchronic toxicity of 4-vinylcyclohexene (VCH). Male and female Sprague-Dawley rats and B6C3F1 mice were exposed by inhalation to VCH 6 hr/day, 5 days/week for 13 weeks. Rats were exposed to 0, 250, 1000, or 1500 ppm, and mice were exposed to 0, 50, 250, or 1000 ppm. In addition, another group of rats and mice was exposed to 1000 ppm butadiene so that a comparison could be made between the two compounds. Exposure to 1000 ppm VCH resulted in deaths of all male mice and 5/10 female mice on Test Days 11 or 12. Three additional female mice exposed to 1000 ppm VCH died prior to study completion. The most notable compound-related clinical sign was lethargy observed in the 1500 ppm VCH-exposed rats and 1000 ppm VCH-exposed mice. Male rats exposed to 1500 ppm VCH had significantly lower body weights compared to controls, and male and female rats in the 1500 ppm group had significantly lower body weight gains. None of the VCH-exposed animals or butadiene-exposed rats showed any compound-related hematological effects. However, mice exposed to 1000 ppm butadiene exhibited mild macrocytic anemia. Clinical chemistry evaluation and urinalysis showed no compound-related effects in rats exposed to either VCH or butadiene. Male and female rats exposed to 1000 or 1500 ppm VCH or 1000 ppm butadiene had increased absolute and/or relative liver weights, and male rats in these same exposure groups had increased relative kidney weights. Microscopically, increased accumulation of hyaline droplets was observed in the kidneys of male rats from all VCH exposure groups. Although compound-related, the droplets were not accompanied by cytotoxicity. In mice, the most notable adverse histopathological effect was ovarian atrophy in females exposed to 1000 ppm VCH or 1000 ppm butadiene. The atrophy was slightly more severe in the VCH-exposed females than in the butadiene-exposed females. There were no other compound-related pathological effects in male or female mice exposed to VCH. Additionally, butadiene-exposed male mice had decreased testicular weights, accompanied by slight testicular degeneration and atrophy. For VCH exposure, the no-observed-adverse-effect-level is 1000 ppm for rats based on lethargy and lowered body weights and 250 ppm for mice based on mortality and ovarian atrophy.

Administration, Inhalation↗
PubMed1991

Tumor-promoting activity of ethyl phenylpropiolate.

The ability of the hyperplasiogenic irritant ethyl phenylpropiolate (EPP) to act as a tumor promoter in two-stage carcinogenesis and to stimulate cellular events commonly cited as markers of tumor promoter action was evaluated. Treatment of adult, inbred SENCAR (SSIN) mice, initiated with 7,12-dimethylbenz(a)anthracene, with 5 mg of EPP twice weekly resulted in 100% of the mice developing tumors (4.8 tumors/mouse) after 40 weeks of promotion. Treatment with 3 mg EPP (twice weekly) resulted in 52% of the mice developing tumors (0.9 tumor/mouse). This treatment regimen with EPP produces a sustained epidermal hyperplasia without being overtly toxic. In addition, a 5-mg dose of EPP induced ornithine decarboxylase activity to a level comparable to that induced by the tumor promoter phorbol 12-myristate 13-acetate (PMA): 2.3 nmol CO2/mg protein/h for EPP versus 4.5 nmol CO2/mg protein/h for PMA versus 0.04 nmol CO2/mg protein/h for acetone control. Likewise, the time course of ornithine decarboxylase induction by EPP was the same as that seen with PMA (maximum induction at approximately 6 h). Vascular permeability of the dorsal skin increased significantly in response to EPP (8 times that seen in acetone controls) and exhibited the same kinetics as that seen after exposure to PMA. Activity of protein kinase C (PKC), the cellular receptor for PMA, decreased by 75 to 95% 48 h after treatment with PMA. In contrast, EPP treatment resulted in less than a 20% decrease in PKC activity 48 h after treatment. This slight decrease in PKC activity is thought to be an indirect effect caused by the hyperproliferative and inflammatory reactions, because EPP was found to be inactive as an in vitro activator of PKC. These results indicate not only that EPP is a good tumor promoter that causes morphological and biochemical responses similar to those induced by PMA, but also that the action of EPP is apparently mediated via a mechanism that does not involve direct interaction with PKC.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Quality assurance and quality control in toxicology: how might these concepts apply to epidemiology?

Quality assurance and its distinction from quality control are defined in operational terms. The historical development of standards for scientific research supporting commercialization of materials leading to the current Good Laboratory Practice (GLP) standards is briefly outlined. The application of GLPs to toxicology studies and experience in the use of these standards over a broad range of activities is also presented. This background information provides a common starting point for consideration of the development and application of similar standards for epidemiological studies.

Epidemiologic Methods↗
PubMed1991

Quality assurance for epidemiologic studies.

Quality assurance (QA) has been successfully applied to scientific disciplines such as toxicology. Experience gained in the application of QA and quality control (QC) through a formal program of compliance with Good Laboratory Practice (GLPs) regulations has been beneficial in toxicology and can be used to develop and implement a similar program in epidemiology. We focus here on the specific ways in which GLP-mandated quality assurance can be adapted and used in epidemiology and on the consequent benefits of this effort.

Cost-Benefit Analysis↗
PubMed1991

Issues in data sharing and access: an industry perspective.

Epidemiologic data sharing and access, and information sharing and access, are complex issues with no consensus within the industrial community. The purpose of this paper is to provide an introduction, as well as some personal perspectives, to the issues of data access and sharing. These perspectives include a discussion of types of data sharing, advantages and barriers to openness, and alternatives that lower the need for sharing of the raw data.

Confidentiality↗
PubMed1990

Arachidonic acid metabolism varies with the state of differentiation in density gradient-separated mouse epidermal cells.

Epidermal cells were isolated from adult inbred SENCAR (SSIN) mice and separated by density-gradient centrifugation. The cells were pooled into three fractions shown by previous work to differ in their state of differentiation and proliferative potential. The three fractions were examined for their capacity to metabolize exogenous 14C-arachidonic acid (AA) into prostaglandins (PG) and hydroxyeicosatetraenoic acids (HETE). Cells found in the upper two fractions, which are less dense, have less proliferative potential in vitro, and are more differentiated than cells in the lower more dense fraction, are much more active in producing PG from exogenous AA than are the more dense cells. This was observed in intact cells as well as cells disrupted by freeze-thawing following density separation. The same relationship was found for HETE production in that cytoplasmic preparations from the two fractions containing the less dense cells were much more active in the production of HETE than cytoplasmic preparations from the more dense fraction. The two upper fractions differed little from each other in the production of PG or HETE. These results indicate the presence of higher levels of active cyclooxygenase and lipoxygenases in fractions containing the less dense, more differentiated cells than in the fraction containing the more dense, less differentiated cells which are highly enriched for basal keratinocytes.

Animals↗
PubMed1989

Correlation of phorbol ester promotion in the resistant C57BL/6J mouse with sustained hyperplasia but not ornithine decarboxylase or protein kinase C.

The activation of protein kinase C, induction of ornithine decarboxylase (ODC), and hyperplasia have been suggested to be linked, sequential processes resulting from phorbol ester application to mouse skin. However, evidence is presented indicating that these events are not necessarily linked or dependent on one another and that significant differences exist in these responses between phorbol ester promotion sensitive (SSIN) and resistant (C57BL/6J) mice. The epidermis from SSIN mice treated with a single application of 12-O-tetradecanoylphorbol-13-acetate (TPA) displayed a large induction of ODC and a subsequent extensive hyperplasia. A second TPA treatment at 24 or 48 h after the first did not result in ODC induction (refractory state), and protein kinase C was shown to be down-regulated at these times. By 72 h, however, a responsive state had returned even through protein kinase C remained down-regulated. The epidermis of C57BL/6J responds to a single application of TPA with a level of ODC induction similar to that of the SSIN mice. Protein kinase C was down-regulated by approximately 75% after 24 h and was virtually completely down-regulated at 48 and 72 h (95-97%). In contrast to the above findings for the sensitive mice, however, little, if any, hyperplasia was produced. In addition, while a second TPA treatment at 24 h did not result in ODC induction (refractory state), hyperplasia did occur within 24 to 48 h. When the second TPA application was given 48 h after the first, at a time when protein kinase C was down-regulated, an overinduction of ODC occurred, as well as subsequent hyperplasia. Furthermore, a significant number of papillomas resulted when these increased treatment frequencies, i.e., once a day or every other day, were used to promote dimethylbenz(a)anthracene-initiated C57BL/6J mice. It is concluded that, while hyperplasia remains an apparent requirement for tumor promotion, the ODC induction following an initial TPA treatment is insufficient for or not causally related to this hyperplasia. In addition, subsequent ODC induction, at least in the C57BL/6J mouse, is probably not mediated by protein kinase C.

Animals↗
PubMed1988

Phorbol ester induction of 8-lipoxygenase in inbred SENCAR (SSIN) but not C57BL/6J mice correlated with hyperplasia, edema, and oxidant generation but not ornithine decarboxylase induction.

Several responses suggested to be critical components of phorbol ester tumor promotion were compared in 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion-sensitive SSIN and TPA promotion-resistant C57BL/6J mice. SSIN mice treated topically with 2 micrograms of TPA showed extensive hyperplasia accompanied by edema, measured as a 26% increase in water content of the skin. Only a very slight hyperplasia and 7% increased water content occurred after TPA treatment of C57BL/6J mice. The induction of ornithine decarboxylase was determined to be the same both in vivo and in vitro for SSIN and C57BL/6J mice, which does not correlate with the histological observations. Because hyperplasia and inflammation can be mediated by arachidonic acid metabolites, it was hypothesized that differences in this metabolic pathway would correlate with the histological responses. No significant qualitative or quantitative differences, however, were observed in the profiles of the major cyclooxygenase products between the strains of mice. Prostaglandin E2, the principal prostaglandin, was synthesized at a 3-fold greater level than prostaglandins D2 or F2 alpha in response to TPA. The most abundant lipoxygenase product was 12-hydroxyeicosatetraenoic acid followed by 8-, 15-, and 5-hydroxyeicosatetraenoic acid. 8-Lipoxygenase activity is elevated 24 h after TPA treatment in the SSIN mice by approximately 4-fold; no elevation is seen in C57BL/6J mice. A comparison of the oxidant response to TPA as well as to phospholipase C showed that SSIN epidermal cells generated a higher level, measured by chemiluminescence, than C57BL/6J cells. This suggests that oxidant generation or possibly 8-lipoxygenase activity may be the basis for the sensitivity or resistance to TPA as a hyperplasiogen and as a tumor promoter.

Animals↗
PubMed1988

Reactive oxygen in the tumor promotion stage of skin carcinogenesis.

Exposure of isolated SENCAR mouse epidermal cells to the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA) in vitro resulted in the production of oxidant species detected as chemiluminescence. This oxidant response can be inhibited by superoxide dismutase and copper complexes but not catalase or scavengers of hydroxyl radical or singlet oxygen, suggesting that the oxidant is superoxide anion. Inhibitors of various parts of the arachidonate cascade affect the TPA-induced oxidant response in a manner that corresponds to their effects on in vivo tumor promotion experiments. Agents that inhibit lipoxygenase activity, i.e. nordihydroguaiaretic acid, benoxaprofen, but not agents that are cyclooxygenase inhibitors, i.e. indomethacin, are effective in suppressing the oxidant response to TPA. Phospholipase C but not phospholipase A2 or D produced an oxidant response kinetically similar to that elicited by TPA. The inhibitors of TPA-induced oxidants inhibited the phospholipase C response to the same extent, suggesting that TPA and phospholipase C may produce an oxidant species through a common mechanism, via phospholipid turnover-protein kinase C activation. The relevance of oxidant production to the tumor promotion process is suggested by the ability of exogenous xanthine/xanthine oxidase, a superoxide anion-generating system, to induce ornithine decarboxylase, a characteristic of TPA-treated cells. In addition, oxidant production is significantly lower in cells from the TPA-promotion resistant C57BL/6J mouse. These studies provide further support for a role for reactive oxygens in the tumor promotion process.

Animals↗
PubMed1987

A new medium for primary cultures of adult murine epidermal cells: application to experimental carcinogenesis.

A culture medium has been formulated to support the long-term proliferation and differentiation of normal murine epidermal cells in primary cultures. This formulation is based upon MCDB-151 modified by the addition of 1.2 mM Ca2+, 1% fetal bovine serum (FBS) or 0.1% purified bovine serum albumin (BSA), trace elements, and growth supplements. For 4-12 weeks, the cultures demonstrate desmosomes, keratin fibers, basal proliferation, and stratification characteristic of keratinocytes. The addition of 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in approximately 70% cellular detachment, but with continued treatment, the remaining cells proliferated to confluence and stratified. This culture medium has application to a number of studies related to skin carcinogenesis in the murine model system that have not previously been possible.

Animals↗
PubMed1987

Possible dissociation of the phorbol ester-induced oxidant response and tumor promotion in the F1 offspring of SSIN x C57BL/6J mice.

The F1 progeny of a cross between 12-O-tetradecanoyl-phorbol-13-acetate (TPA) tumor promotion-sensitive SSIN mice and TPA promotion-resistant C57BL/6J mice were found to be sensitive to TPA as a tumor promoter. The tumor response was substantial, with an average of 15 papillomas per mouse and a 100% incidence following initiation with 400 nmol dimethylbenz[a]anthracene and promotion with 6.5 nmol (4 micrograms) TPA. To determine whether tumor promotability of the F1 mice correlates with other parameters believed to be associated with TPA responsiveness, oxidant generation, epidermal hyperplasia and edema were compared in the parents and F1 hybrids. The SSIN produced a strong hyperplastic response to TPA, the C57BL/6J a negligible response and the F1 hybrids a moderate response. In the SSIN, 6.5 nmol (4 micrograms) TPA caused an 18% increase in the water content of the skin (edema) while no change was seen for either the C57BL/6J or F1 hybrids. The oxidant response of the F1 hybrids to either TPA or phospholipase C was markedly less than that observed for the SSIN and was similar to the response previously observed for the C57BL/6J mice. These findings suggest that the oxidant response may not be an essential aspect of TPA tumor promotion. It may be related to the edema response, suggesting that at least this aspect of inflammation is not necessary for promotion.

Animals↗
PubMed1986

Effects of anti-promoters and strain of mouse on tumor promoter-induced oxidants in murine epidermal cells.

The induction of oxidant production in mouse epidermal cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) can be suppressed by many, but not all, known inhibitors of mouse skin tumor promotion. Members of the anti-oxidant category that were tested were ranked in the following order, 7,8-benzoflavone greater than butylated hydroxyanisole greater than ascorbic acid. In the retinoid category, retinoic acid was only moderately effective, while the trimethoxymethylphenyl analog had at least twice the inhibitory activity. Among the six protease inhibitors examined, tosylphenylalanine chloromethylketone and tosyllysine chloromethylketone were effective in diminishing the response while tosylarginine methylester, antipain, leupeptin and soybean trypsin inhibitor were ineffective, suggesting that proteases are probably not involved in the oxidant response. Several agents, trifluoperazine, trisialoganglioside and diolein, that have been shown to suppress TPA activity in other cell systems were also found to suppress the oxidant response. Finally, the extent of the oxidant response was found to correlate with sensitivity to TPA tumor promotion among the three strains of mice tested: SSIn greater than SENCAR greater than C57BL/6J.

Animals↗
PubMed1985

Phospholipase C mimics tumor promoter-induced chemiluminescence in murine epidermal cells.

Treatment of newborn murine epidermal cells with phospholipase C results in the generation of a chemiluminescence response similar to that previously described for phorbol ester tumor promoters. Based on inhibitor studies, the oxidant, believed to be superoxide anion, is most likely generated from lipoxygenase metabolism of arachidonic acid. The specificity of the response to phospholipase C from C. perfringens and not from B. cereus or phospholipase A2 suggests specific phospholipids are involved. The response observed appears to arise from the phospholipid-protein kinase c model for phorbol ester binding and activity.

Animals↗
PubMed1985

Nitrogen balance studies in aging rats.

Nitrogen balance studies were conducted to compare the protein requirements of aged (24-month-old) and mature (12-month-old) rats for possible age-related differences. Four diets with protein supplied as amino acid mixtures simulating casein protein at 4.5%, 4.5% plus 1.5% indispensable amino acids of casein, 4.5% plus 1.5% dispensable amino acids of casein or 6.0% casein protein were offered for one week each during a four-week counter-balanced dietary sequence. Lower food and nitrogen intake of aged rats resulted in a lower mean nitrogen balance compared to that of the mature animals. Calculations of the level of N intake necessary to provide for N equilibrium in the aged rats indicated an apparent increase in the actual net need for nitrogen and indispensable amino acids when compared with the needs of the mature animals.

Age Factors↗
PubMed1980

Teratogenic activity in the mouse after oral administration of acetazolamide.

Acetazolamide was administered orally by gavage to pregnant mice twice a day on days six through 15 of gestation at a dose level of 300.0 mg/kg. This treatment produced maternal toxicity as evidenced by significantly reduced food consumption and body weight gain. Embryotoxicity demonstrated by significant reductions in fetal weight and crown-rump length was also observed. Resorption rates were considerably higher (77.9%) for the acetazolamide treated litters when compared to those from the control group (8.23%). A variety of malformations was observed in the acetazolamice-treated rats (rib and vertebral fusion, gastroschisis, tail defects, cleft palate and ectrodactyly). These results further establish acetazolamide as an acceptable positive teratogenic control by demonstration of species and strain susceptibility in the CD-1 mouse.

Abnormalities, Drug-Induced↗