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Biomedical subjects

A L Kraus

Publications and source records attributed to A L Kraus.

At least 19 recordsLinked to original sources
PubMed1997

Percutaneous penetration of octyl salicylate from representative sunscreen formulations through human skin in vitro.

The human skin penetration of [14C]octyl salicylate from two representative sunscreen vehicles was determined in vitro. 3H-sucrose was incorporated into all formulations and provided a marker for membrane integrity. When applied as a finite dose in an oil-in-water emulsion vehicle containing 5% (w/w) octyl salicylate, the average total absorption of 14C over 48 hr was 0.65+/-0.16% of the applied dose (representing a total amount permeated of 1.58+/-0.36 microg/cm2). When applied as an infinite dose in the oil-in-water emulsion vehicle the average total absorption of 14C over 48 hr was 0.47+/-0.22% of the applied dose (representing a total amount permeated of 27.54+/-13.91 microg/cm2). When applied as a finite dose in a representative hydroalcoholic formulation containing 5% (w/w) octyl salicylate, the average total absorption of 14C over 48 hr was 0.59+/-0.09% of the applied dose (representing a total amount permeated of 1.58+/-0.25 microg/cm2). When applied as an infinite dose in the hydroalcoholic formulation the average total absorption of 14C over 48 hr was 0.23+/-0.05% of the applied dose (representing a total amount permeated of 11.28+/-2.55 microg/cm2). The penetration of [14C]salicylic acid [applied at a concentration of 2.7% (w/w), in the oil-in-water emulsion] was also determined. When applied as a finite dose the average total absorption of 14C over 48 hr was 1.14+/-0.23% of the applied dose (representing a total amount permeated of 1.65+/-0.39 microg/cm2). These results suggest that the in vitro human skin permeation of octyl salicylate is relatively low. The amounts of octyl salicylate and salicylic acid permeated when applied in similar vehicles were remarkably similar over 48 hr (1.58 microg/cm2 and 1.65 microg/cm2, respectively). This suggests the possibility that the 14C label appearing in the receptor fluid may, in both cases, represent salicylic acid. If this is the case, then it is possible that the amount of octyl salicylate permeating through the skin is much less than that suggested by the data obtained here. This supposition is, however, entirely speculative and has yet to be confirmed experimentally.

Administration, Cutaneous↗
PubMed1997

Percutaneous absorption of salicylic acid after repeated (14-day) in vivo administration to normal, acnegenic or aged human skin.

The objective of the present work was to determine the relative bioavailability of salicylic acid (SA) after repeated (14-day) topical application to subjects who presented normal, acnegenic, or photodamaged facial skin. To emulate exposure characteristics likely to be encountered by subjects in these two subpopulations, individuals presenting facial acne were treated with 2% SA in a hydroalcoholic vehicle, and volunteers with aged or photodamaged skin received a comparable topical dose of SA in a cream (moisturizer-like) vehicle. Plasma concentration-time profiles and cumulative urinary excretion of SA were measured after the last dose in subjects who had received 15 consecutive daily topical applications of 27 mg of SA or oral doses of 81 mg of acetylsalicylic acid (ASA). The rate and extent of percutaneous absorption of SA were not affected by facial skin condition. Faster rates of absorption (Cmax) were obtained with a hydroalcoholic compared with a cream vehicle. Systemic SA exposures were at least five-fold higher with oral ASA than topical SA. Based on systemic salicylate concentrations resulting from ingestion of 81 mg of ASA, these results support that patients without gross skin disorders are at minimal risk of adverse systemic effects from routine use of topical products containing 2% SA.

Acne Vulgaris↗
PubMed1996

A toxicological review of topical exposure to white mineral oils.

White mineral oils have a long history of safe use by humans in orally ingested and topically applied products. A re-evaluation of the use of certain mineral hydrocarbons in the preparation of food items by regulators in the UK, however, has prompted additional safety studies and a critical assessment of the toxicological effects of white mineral oils. As white mineral oils are present in many topically applied drug and non-drug products, it is of interest to review the toxicological effects of mineral oil produced by this route of exposure. Specifically, the concern regarding the safety of white mineral oils has arisen, in part, from results of subchronic (e.g 90 day) feeding studies that reported the presence of granulomas in liver and histiocytosis in mesenteric lymph nodes of Fischer 344 rats after oral ingestion of select white mineral oils. In contrast to these subchronic oral studies, repeated topical exposure to white mineral oils has not been found to produce liver granulomas, histiocytosis in the mesenteric or other lymph nodes, or any local or systemic toxicity including tumour formation in Fischer 344 rates, C3H mice, New Zealand White rabbits or beagle dogs at similar or higher exposures (mg/kg/day). On the basis of these findings and reports on negligible epidermal penetration of topically applied white mineral oils, there is no evidence of any hazard identified for topical exposure to white mineral oils at any dose in multiple species. This conclusion is supported by the long and uneventful human use of white mineral oils in drug and non-drug topically applied products.

Administration, Oral↗
PubMed1996

Maternal reproductive effects of oral salicylic acid in Sprague-Dawley rats.

Clinical and experimental evidence indicates that exposure to relative ly large doses of acetylsalicylic acid (ASA) prolongs parturition. However, little is known about the dose-response relationship for salicylate-related effects on labor and gestation. As well, the relative potency of salicylic acid (SA) as compared with ASA for these reproductive effects has not been well investigated. This study was designed to define a dose-response relationship for salicylic acid (SA) effects on labor and gestation times in Sprague-Dawley rats. Pregnant females received oral doses of 20,80, or 200 mg/kg/day sodium salicylate, or 260 mg/kg/day acetylsalicylic acid (ASA), as a positive control, on days 15 through 21 of gestation (sperm positive = day 0). Onset of labor was followed in each animal beginning on day 21 of gestation. The data failed to demonstrate a substantial potency difference between ASA and SA but some differences in toxicity were observed. Relative to controls, gestation times were unaffected by SA. SA treatment resulted in a dose-related trend towards increased duration of labor which was statistically significant at 200 mg/kg/day of SA. ASA treatment of pregnant females resulted in both prolonged labor and gestation times. Both the highest administered dose of SA and ASA treatment contributed to increased maternal peripartum death. Overall, the study confirms a dose-response relationship for SA-induced maternal reproductive effects and supports a no observable effect level (NOEL) for this compound of 80 mg/kg/day for adverse effects on parturition.

Administration, Oral↗
PubMed1996

Analysis of rodent photo cocarcinogenicity models for hazard evaluation and risk assessment: industry viewpoint.

The general consensus in industry is that photo cocarcinogenicity models are experimental and may prove problematic for use as toxicological tools in routine compound development. Part of the reason for this is the fact that current designs yield similar study outcomes from multiple underlying activities (e.g. photoactivation vs tumor promotion) that can be considered of very different importance in IARC and OSTP human cancer risk assessment approaches. Importantly, photoactivation concerns are significant and, therefore, a decision scheme needs to be developed based on data to ensure that activities of this type do not go undetected. Assuming that this approach includes rodent photo cocarcinogenicity models at some level, then an increased level of understanding of the role of these rodent results in determination of any possible human health impact needs to be made. Learning about the mechanism of action from historical multistage carcinogenesis models will likely prove to be important in this process. Finally, given significant current uncertainty in extrapolation from mouse cocarcinogenicity models to humans, epidemiological data need to be used whenever possible to both test the utility of the model and ensure appropriate market decisions where possible.

Animals↗
PubMed1995

Benzoyl peroxide: an integrated human safety assessment for carcinogenicity.

Topical benzoyl peroxide has been used in the treatment of acne for over 30 years, with no reports of adverse effects that could be related to skin carcinogenesis. Two case-control epidemiological studies have found a lack of association between the specific use of benzoyl peroxide and skin cancer. In addition to these findings in humans, 23 carcinogenicity studies in rodents with benzoyl peroxide, including 16 employing topical application, have yielded negative results. An increase in skin carcinomas was reported in 1 study in which benzoyl peroxide in acetone was applied to the skin of SENCAR mice for a 1-year period; however, this study did not employ adequate control groups to fully understand the unusual findings, and the results were inconsistent with those of 6 other similar studies. While benzoyl peroxide is not a complete carcinogen in animals and has weak or no mutagenic potential, it has been found to be a tumor promoter in mouse skin using experimental two-stage models of carcinogenesis. Consistently positive results have been obtained in tumor promotion studies in which SENCAR mice were exposed to initiating doses of potent experimental carcinogens followed by promotion with benzoyl peroxide in acetone. Negative results have been obtained in similar studies with commercial formulations. However, the results of promotion studies with benzoyl peroxide do not carry significant weight for human safety assessment as evidenced by (i) the absence of demonstrated carcinogenicity in humans of a number of rodent tumor promoters despite long-term human exposure; (ii) the observation that tumor promotion in mouse skin occurs only under specific experimental conditions and predominantly in highly sensitive strains; (iii) clinical use scenarios markedly different from the conditions resulting in tumor promotion in mouse skin; and (iv) the significant physiological differences between mouse and human skin. Thus, to date, available scientific evidence does not allow the results of these rodent promotion studies to be meaningfully applied to human safety assessment. As such, significant scientific progress must be made before human safety estimations can be derived from rodent promotion data.(ABSTRACT TRUNCATED AT 400 WORDS)

Acne Vulgaris↗
PubMed1994

Assessment of the in vivo genotoxicity of 2-hydroxy 4-methoxybenzophenone.

The genotoxic potential of 2-hydroxy 4-methoxy-benzophenone (benzophenone-3, Bz-3), a commonly used sunscreen, has been evaluated previously with in vitro systems. Data from Salmonella studies (with and without activation) have been predominantly negative, but two reports have shown weakly positive results in a single bacterial strain under conditions of metabolic activation. In addition, Bz-3 has been reported to induce chromosome aberrations and equivocal results for sister chromatid exchange in Chinese hamster ovary (CHO) cells. We used the Drosophila somatic mutation and recombination test (SMART) and in vivo cytogenetics in rat bone marrow to define the potential for in vivo expression of this in vitro activity. For the SMART assay, larva from a mating of "multiple wing hair" (mwh) females with heterozygous "flare" (flr) males were exposed to 0, 3000, or 3500 ppm Bz-3 or 25 ppm dimethylnitrosamine (DMN, positive control) for 72 hr. A recombination between the mwh and flr genes produces twin wing spots, while events such as deletions produce single spots. None of the Bz-3-treated larva produced flies with significantly more single or multiple wing spots than controls. In contrast, DMN-treated larva produced flies with significantly more single or multiple wing spots than controls. The in vivo cytogenetic assay in rat bone marrow cells was conducted to evaluate the clastogenicity of Bz-3. Sprague-Dawley rats were treated by oral gavage with a single administration of 0.0, 0.5, 1.67, or 5 gm/kg Bz-3 or a single dose of 5 gm/kg/day Bz-3 for 5 consecutive days. Cyclophosphamide (CP) was the positive control and was administered at 20 mg/kg with both treatment regimens. Colchicine growth-arrested bone marrow cells were collected 8 and 12 hr after the single treatment and 12hr after the last daily treatment. Under either treatment protocol none of the Bz-3 concentrations caused any significant increase in chromosomal aberrations. Results from these two studies strongly support the conclusion that Bz-3 is not genotoxic in vivo.

Animals↗
PubMed1994

Evaluation of subchronic (13 week), reproductive, and in vitro genetic toxicity potential of 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate (Octocrylene).

Use of 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate (Octocrylene) in commercial sunscreen products has increased considerably in recent years. To support larger scale human exposure to this compound, additional toxicological information was needed in several key areas. The present studies evaluated subchronic toxicity, developmental toxicity, and in vitro genotoxic potential of Octocrylene. In the subchronic study, male and female New Zealand white (NZW) rabbits treated topically with concentrations of octocrylene up to 534 mg/kg/day for 13 weeks showed slight to moderate dose-dependent skin irritation that correlated positively with a mild depression in body weight gain. Lack of associated histopathologic or clinical hematology abnormalities suggested that the body weight effect probably reflected a nonspecific response to topical irritation. In percutaneous developmental toxicity studies, NZW does were treated topically with Octocrylene at levels up to 267 mg/kg/day on Days 6 through 18 of gestation. Body weight gain, food consumption, and all maternal, reproductive, and offspring parameters evaluated were comparable between Octocrylene-treated and control animals. In the oral developmental toxicity assay, female CD-1 mice received oral doses of Octocrylene up to 1000 mg/kg/day on Days 8-12 of gestation. No evidence of maternal or developmental toxicity was seen at any dose tested. Genotoxicity was evaluated in vitro using the Chinese hamster ovary cell assay to assess clastogenicity and the mouse lymphoma cell assay to assess forward gene mutations. Octocrylene did not induce any significant increase in genotoxicity. This evaluation of toxicological potential supports the use of Octocrylene as a human photoprotectant.

Acrylates↗
PubMed1994

Comparative efficacy of sunscreen reapplication regimens in children exposed to ambient sunlight.

Undercompliance with sunscreen reapplication recommendations is a probable factor in suboptimal childhood ultraviolet radiation (UVR) protection. However, improving on the ability of sunscreens to absorb UVR without requiring frequent reapplication is difficult because the models most frequently used to develop and evaluate photoprotectants have only a limited ability to incorporate behavioral and environmental variables that are primarily responsible for loss of sunscreen efficacy. Hence, the objective of the present work was to develop a method to evaluate the efficacy of various regimens of sunscreen reapplication in children, under conditions of unrestricted behavior and exposure to ambient sunlight. Ninety-eight children, ages 7-12, Fitzpatrick skin types I-III, were divided between two study groups. The majority were types I-II, and all types were approximately equally represented between the groups. The children received single or multiple applications of a sun protection factor 25 sunscreen to preassigned lateral halves of the body and engaged in unrestricted activities throughout a 6- (group I) or 8-h (group II) period of sun exposure at a seaside location. The end measurement for these studies was incidence and severity of erythema 18 to 22 h after peak UV exposure. The results obtained showed that 1 or 4 sunscreen applications yielded comparable erythema protection after a 6-hour sun exposure, totaling 13 minimal erythema doses (MED). However, after an 8-h, 21 MED exposure, incidence and severity of erythema was greater at body sites treated with 1 compared with 5 sunscreen applications.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylates↗
PubMed1993

Assessment of the reproductive toxic potential of dermally applied 2-hydroxy-4-methoxybenzophenone to male B6C3F1 mice.

The potential of 2-hydroxy-4-methoxybenzophenone (HMB) to cause male reproductive toxicity was assessed in B6C3F1 mice. HMB was administered topically for 13 weeks (5 days/week) to groups of 10 mice each at dosages of 0, 10, 20, 100, or 400 mg/kg/day. Additional high dosage and control mice were also included and euthanized at interim time points to characterize the time course of any effects. After 91 days (or at interim periods) mice were euthanized and reproductive organ weights, cauda epididymal sperm concentration and proportion of motile and abnormal sperm, and testicular spermatid concentration were determined. Testicular histology was evaluated in fixed tissue. HMB treatment had no effect on body weight gain or any of the male reproductive parameters assessed at any time point. These results indicate that topically applied HMB has no reproductive toxic potential in male B6C3F1 mice at dosages as high as 400 mg/kg/day.

Administration, Topical↗
PubMed1991

Immune modulation in the guinea pig using cortisone acetate.

Cortisone acetate was administered to a group of guinea pigs (Cavia porcellus) at 0 (control), 20 (low) or 200 (high) mg/kg. Steroid was given daily for two individual 7 day periods, separated by 7 days of no treatment. The effects of this steroid on body weight gain, thymic weight, total and differential leukocyte counts, serum antibody titer against a bacterin, dermal hypersensitivity response to a sensitizing agent and histological evaluation of lymphoid and other tissues were evaluated. Significant differences in body weight gain (p less than 0.05) and thymic weight (p less than .01) were noted. For total leukocyte count, no significant difference among treatment groups at individual time points was noted (p greater than .10), while significant differences were seen in lymphocyte and neutrophil counts (p less than .01). A significant difference in antibody titer among the treatment groups was observed (p less than .01). For the dermal hypersensitivity response, there was no consistent pattern among the treatment groups in gross (macroscopic) skin reactions. Microscopically, differences were seen in the inflammatory response among the treatment groups. Histologically, steroid related changes were seen in thymus, spleen, lymph node and liver. At necropsy, 24 of 40 animals had lesions of focal necrotizing hepatitis. Three affected animals died and remaining animals showed no clinical illness. The cause of the necrotizing hepatitis could not be determined by culture, special stains, electron microscopy, serology or by attempts at transmission with affected liver samples.

Animals↗
PubMed1990

Allergic contact dermatitis from propyl gallate: dose response comparison using various application methods.

The antioxidant propyl gallate, in a deodorant product, caused an allergic contact dermatitis in 1 subject during developmental controlled use testing. Subsequent dose response elicitation studies with this subject revealed a differing threshold of sensitivity to propyl gallate dependent upon application method. Increasing the level of occlusion increased the elicitation response. Responsiveness from greatest to least was: occluded patch on the upper arm greater than semi-occluded axilla greater than open application on the antecubital fossa. The thresholds determined for propyl gallate (w/v in 25:75 ethanol:water) were: (a) 0.0025% for the upper arm occluded patch; (b) 0.0035% for the underarm without shaving; (c) 0.005% for the underarm with shaving; (d) 0.015% for the antecubital fossa. Occluded patch responsiveness to propyl gallate was monitored and remained unchanged throughout a 2-year period. These data are useful in understanding the relationship between occlusive allergic contact dermatitis patch testing and clinical contact dermatitis.

Administration, Cutaneous↗
PubMed1989

Human lipoprotein influence on the partition of 2,2',4,4',5,5'-hexabromobiphenyl between 3T3L1 adipocytes and culture medium.

A previous study established that 2,2',4,4',5,5'-hexabromobiphenyl (HBB) entered 3T3L1 adipocytes in culture by passive diffusion from the surrounding medium. The extent to which HBB accumulated within the cell was mediated by the level of triglyceride in the cell. The present study was concerned with the conditions that would facilitate HBB removal from adipocytes as part of a continuing effort to establish an effective and safe technology for reducing body burdens of lipophilic xenobiotics. Addition of human lipoprotein to the culture medium increased HBB removal from preloaded adipocytes 18 to 80 times more than did the addition of other blood proteins. Lipoproteins also decreased equilibrium deposition of HBB in the cells. The order of effect was low-density lipoprotein (LDL) much greater than high-density lipoproteins (HLD) greater than very-low-density lipoproteins (VLDL). These results are consistent with the hypothesis that lipoproteins act as a depot by binding HBB to immobilize the xenobiotic in the medium. The rate of removal of HBB was correlated with concentrations of lipoprotein cholesterol, cholesterol ester, and phospholipid in the culture medium (r greater than .95). Total lipoprotein fractions from individuals with high levels of serum cholesterol significantly increased HBB removal from preloaded adipocytes when compared with lipoproteins from normal human serum. Decreased removal was observed with lipoproteins from individuals with low serum cholesterol or triglyceride. These results suggest that cholesterol and/or cholesterol esters in the blood play an important role in both delivery and removal of HBB from the adipose tissue. Evidence has been presented that supports the hypothesis that HBB moves freely across the adipocyte membrane and is sequestered in either the cell or pseudoblood according to its relative solubility in these compartments.

Adipose Tissue↗