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1.
Regul Toxicol Pharmacol ; 88: 144-156, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28559157

ABSTRACT

In order to accurately assess aggregate exposure to a fragrance material in consumers, data are needed on consumer habits and practices, as well as the concentration of the fragrance material in those products. The present study describes the development of Phase 2 Creme RIFM model by expanding the previously developed Phase 1 model to include an additional six product types. Using subject-matching algorithms, the subjects in the Phase 1 Creme RIFM database were paired with subjects in the SUPERB and BodyCare surveys based on age and gender. Consumption of the additional products was simulated to create a seven day diary allowing full data integration in a consistent format. The inhalation route was also included for air care and other products where a fraction of product used is inhaled, derived from the RIFM 2-box model. The expansion of the Phase 1 Creme RIFM model has resulted in a more extensive and refined model, which covers a broader range of product categories and now, includes all relevant routes of exposure. An evaluation of the performance of the model has been carried out in an accompanying publication to this one.


Subject(s)
Algorithms , Cosmetics , Habits , Adult , Aerosols , Consumer Product Safety , Cosmetics/chemistry , Female , Hair Preparations/chemistry , Humans , Inhalation Exposure , Male , Matched-Pair Analysis , Middle Aged , Perfume/chemistry , Soaps/chemistry
2.
Regul Toxicol Pharmacol ; 72(3): 660-72, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26003515

ABSTRACT

Exposure of fragrance ingredients in cosmetics and personal care products to the population can be determined by way of a detailed and robust survey. The frequency and combinations of products used at specific times during the day will allow the estimation of aggregate exposure for an individual consumer, and to the sample population. In the present study, habits and practices of personal care and cosmetic products have been obtained from market research data for 36,446 subjects across European countries and the United States in order to determine the exposure to fragrance ingredients. Each subject logged their product uses, time of day and body application sites in an online diary for seven consecutive days. The survey data did not contain information on the amount of product used per occasion or body measurements, such as weight and skin surface area. Nevertheless, this was found from the literature where the likely amount of product used per occasion or body measurement could be probabilistically chosen from distributions of data based on subject demographics. The daily aggregate applied consumer product exposure was estimated based on each subject's frequency of product use, and Monte Carlo simulations of their likely product amount per use and body measurements. Statistical analyses of the habits and practices and consumer product exposure are presented, which show the robustness of the data and the ability to estimate aggregate consumer product exposure. Consequently, the data and modelling methods presented show potential as a means of performing ingredient safety assessments for personal care and cosmetics products.


Subject(s)
Cosmetics , Environmental Exposure , Models, Theoretical , Perfume , Adolescent , Adult , Aged , Consumer Product Safety , Databases, Factual , Europe , Female , Humans , Male , Middle Aged , United States , Young Adult
3.
Fundam Appl Toxicol ; 22(3): 355-68, 1994 Apr.
Article in English | MEDLINE | ID: mdl-8050631

ABSTRACT

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.


Subject(s)
Acrylates/toxicity , Mutagens/toxicity , Reproduction/drug effects , Sunscreening Agents/toxicity , Acrylates/administration & dosage , Acrylates/pharmacokinetics , Administration, Oral , Administration, Topical , Animals , Body Weight/physiology , CHO Cells , Chromosome Aberrations/genetics , Cricetinae , Female , Male , Mice , Mouth/drug effects , Mouth/growth & development , Mutagenicity Tests , Organ Size/drug effects , Rabbits , Skin Absorption , Sunscreening Agents/administration & dosage , Sunscreening Agents/pharmacokinetics , Tumor Cells, Cultured
4.
Environ Mol Mutagen ; 23(4): 312-7, 1994.
Article in English | MEDLINE | ID: mdl-8013479

ABSTRACT

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.


Subject(s)
Benzophenones/toxicity , Chromosome Aberrations , Mutagenesis , Mutagens/toxicity , Sunscreening Agents/toxicity , Animals , Bone Marrow/drug effects , Bone Marrow Cells , Drosophila melanogaster/drug effects , Female , Male , Mutagenicity Tests , Rats , Rats, Sprague-Dawley , Wings, Animal
5.
J Neurol Sci ; 115(2): 201-7, 1993 Apr.
Article in English | MEDLINE | ID: mdl-8482980

ABSTRACT

We have previously reported reduced ability of ALS fibroblasts to repair genomic DNA damage produced by alkylating agents. This report presents our experience of studying DNA repair in lymphocytes from ALS patients. The repair of N-methylpurines produced by treatment with the alkylating agent, methyl methanesulfonate, was studied in T-lymphocytes from patients with sporadic and familial ALS, and appropriate controls. Repair of damage was quantitated by using alkaline elution for genomic DNA repair, and methoxyamine protection of abasic sites in DNA fragments for gene-specific repair in the dihydrofolate reductase (dhfr) gene, at time points 0, 6 h and 24 h. No significant repair rate differences were observed between ALS and control lymphocytes in either genomic or gene-specific DNA repair. The possible reasons for the discrepancy with our earlier results in lymphocytes and fibroblasts are discussed.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , DNA Repair , DNA/metabolism , Purine Nucleotides/genetics , T-Lymphocytes/metabolism , Aged , Cell Survival , Female , Humans , Male , Methyl Methanesulfonate/pharmacology , Middle Aged , T-Lymphocytes/physiology , Tetrahydrofolate Dehydrogenase/genetics
6.
Mutat Res ; 255(3): 241-6, 1991 Nov.
Article in English | MEDLINE | ID: mdl-1719395

ABSTRACT

The in vivo frequency of mutants resulting from mutation at the hprt locus in human T-lymphocytes was determined with a cloning assay. T-lymphocytes were obtained from 14 individuals diagnosed with schizophrenia and 5 controls. No significant difference in mutant frequency was observed between the 2 groups. In addition, DNA-repair capacity was measured with the unscheduled DNA synthesis technique in lymphocytes from 7 individuals diagnosed with schizophrenia and 7 controls. Repair capacity was determined following treatment with MMS, MNNG, and 20 J/m2 ultraviolet light. No significant differences in DNA repair were observed between the patient and control groups in response to any of the 3 DNA-damaging agents. These results argue against differences between normal and schizophrenic individuals with respect to in vivo mutant frequency or their capacity to repair DNA lesions induced by MMS, MNNG, or ultraviolet radiation.


Subject(s)
DNA Repair , Hypoxanthine Phosphoribosyltransferase/genetics , Mutation , Schizophrenia/genetics , Cloning, Molecular , DNA Replication , Humans , Reference Values , Schizophrenia/enzymology , T-Lymphocytes/enzymology
7.
Mutat Res ; 255(3): 247-56, 1991 Nov.
Article in English | MEDLINE | ID: mdl-1719396

ABSTRACT

Alkylating agent damage was quantified in human T-lymphocytes by calculating gene-specific lesion frequencies and repair rates. At 3 time points after exposure to methyl methanesulfonate (0, 6, and 24 h), T-lymphocyte DNA was extracted, digested with HindIII, and divided into 2 aliquots. Apurinic sites were formed in the DNA fragments of both aliquots by heat-induced liberation of the N-methylpurines. The methoxyamine-treated aliquot provided gene fragments which were refractory to alkaline hydrolysis (full-length fragments), while the fragments in the untreated aliquot were cleaved at apurinic sites by hydroxide. After Southern blotting, lesion frequencies were calculated by comparing the band intensity of the full-length fragment to its unprotected counterpart. The restriction fragments analyzed were from the constitutively active dihydrofolate reductase (dhfr) plus hypoxanthine phosphoribosyltransferase (hprt) genes and from the transcriptionally inactive Duchenne muscular dystrophy gene (dmd). In decreasing order, the fragments containing the most lesions per kb of DNA were: hprt greater than dhfr greater than dmd. T-Lymphocytes from 2 females had 30% more heat-labile N-methylpurines in the active X-linked hprt gene than in the inactive X-linked dmd gene. The lesion frequency found in the male's lone hprt allele was the highest observed. These lesion frequency differences are discussed in terms of chromatin structure. After 6 and 24 h, no significant repair rate differences were observed among the 3 genes.


Subject(s)
DNA Damage , DNA Repair , DNA/drug effects , Hydroxylamines/pharmacology , Hypoxanthine Phosphoribosyltransferase/genetics , Methyl Methanesulfonate/pharmacology , Muscular Dystrophies/genetics , T-Lymphocytes/physiology , Tetrahydrofolate Dehydrogenase/genetics , Transcription, Genetic , Cell Survival/drug effects , Cells, Cultured , DNA/genetics , DNA/isolation & purification , Female , Gene Expression , Humans , Kinetics , Male , Restriction Mapping , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , Time Factors
9.
Mutat Res ; 237(3-4): 153-64, 1990.
Article in English | MEDLINE | ID: mdl-2233819

ABSTRACT

In vitro cultures of human peripheral blood lymphocytes, both unstimulated G0 cells as well as phytohemagglutinin (PHA) stimulated cells, have been used in the investigation of DNA repair following different types of damage, including that induced by ultraviolet light, ionizing radiation, and chemical agents. We report here repair of DNA damage in cultured normal human T-lymphocytes after treatment with the alkylating agents, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or methanesulfonate (MMS), as measured by the alkaline elution technique. T-lymphocytes cultured with different sources of T-cell growth factors (TCGFs) were shown to have similar repair levels, as measured by loss of single-strand breaks. However, diminished repair was observed with in vitro culture age when T-cells were cultured with PHA and TCGF for a 3-week period. Cell-cycle analysis performed on asynchronously growing cultures indicated that differential repair with in vitro aging was not cell-cycle-related. Fluorescence Activated Cell Sorting (FACS) was used to determine the percentages of CD4+ and CD8+ T-cell subsets present during the in vitro culture periods. Cultures consisted primarily of CD4+ cells until day 20 when the percentage of CD8+ cells increased to approximately 50% of the T-cell population. Neither the absolute percentages of CD4+ and CD8+ cells not the CD4+/CD8+ ratios correlated with repair rates of cultured T-cells. Therefore, the observed decreases in the repair of alkylating agent-induced damage are not due solely to the change in the CD4+/CD8+ ratio.


Subject(s)
DNA Damage , DNA Repair , T-Lymphocytes/metabolism , Alkylation , Cell Cycle , Cell Survival , Cells, Cultured , Culture Media , Humans , Methyl Methanesulfonate/pharmacology , Methylnitronitrosoguanidine/pharmacology , Phytohemagglutinins/pharmacology , T-Lymphocyte Subsets , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , T-Lymphocytes/radiation effects , Ultraviolet Rays
10.
Mutagenesis ; 5(2): 169-72, 1990 Mar.
Article in English | MEDLINE | ID: mdl-2188070

ABSTRACT

O6-Methylguanine-DNA methyltransferase (MT) specific activity (fmol/mg protein) was measured in human T lymphocytes which were maintained as exponentially growing cultures from 6 to 17 days. The T lymphocytes were not transformed and were grown under the same conditions used previously for determination of spontaneous human mutant frequencies. Although large inter-individual differences in activity were found, the differences were not attributable to donor age, sex or time in culture. The reported specific activity results, including the age and sex independence, were similar to other laboratories even though non-cultured peripheral blood T lymphocytes were previously used. Since cells from Alzheimer's disease (AD) patients have been shown to be overly sensitive to alkylation damage induced by N-methyl-N'-nitro-N-nitrosoguanine, and since no one has previously assayed MT activity in cells from AD patients, we compared MT activities in cultured T lymphocytes from AD patients, healthy controls and neurological controls. Similar levels of MT specific activity were found in each category analysed.


Subject(s)
Alzheimer Disease/enzymology , Methyltransferases/metabolism , T-Lymphocytes/enzymology , Cell Survival , Cells, Cultured , Humans , Lymphocyte Activation , O(6)-Methylguanine-DNA Methyltransferase
13.
Mutat Res ; 219(4): 247-55, 1989 Jul.
Article in English | MEDLINE | ID: mdl-2770772

ABSTRACT

Alterations in the capacity of a cell to repair DNA lesions play an important role in a number of human diseases. We and others have demonstrated defective DNA repair of alkylation damage in cells from patients with Alzheimer's disease. It has been hypothesized that this defect is related to the cause of Alzheimer's disease and results in the accumulation of lesions in the central nervous system neurons. One prediction of this hypothesis is that in dominantly inherited Alzheimer's disease, the repair defect will be present in half of the offspring of affected patients long before they develop symptoms of the disease. In order to test the hypothesis that decreased DNA repair is responsible for familial Alzheimer's disease and their at-risk offspring we have studied DNA repair in these individuals after exposure of lymphoblasts to alkylating agents. Our results indicate that cell lines from affected patients repair significantly less damage in 3 h than cell lines from healthy controls. A small number of at-risk individuals were also studied and some of these had lower levels of repair, although more cell lines from individuals in this group must be studied. These findings provide further support for defective DNA repair playing a role in the pathogenesis of Alzheimer's disease.


Subject(s)
Alzheimer Disease/genetics , DNA Repair , Adult , Aged , Cell Line, Transformed , Cell Transformation, Viral , DNA/drug effects , DNA/isolation & purification , Female , Humans , Male , Methyl Methanesulfonate , Methylnitronitrosoguanidine , Middle Aged
14.
Mutat Res ; 194(2): 101-8, 1988 Sep.
Article in English | MEDLINE | ID: mdl-3261836

ABSTRACT

The repair of DNA alkylation damage in human cells is poorly understood. We have adapted the alkaline elution technique for use with human peripheral blood lymphocytes in culture. We have also established conditions necessary for short-term culture of human lymphocytes. Lymphocyte growth which can be maintained for up to 30 days is dependent upon irradiated TK6 feeder cells and T-cell growth factor (crude TCGF). The amount of damage induced by a given concentration of methyl methane-sulfonate (MMS) is dependent upon cell number per ml of growth medium. The DNA damage measured, in lymphocytes, by alkaline elution is a composite of single strand breaks and alkali-labile lesions. Repair of this damage after appropriate recovery periods is also detectable. The irradiated feeder TK6 cells do not contribute to the number of strand breaks detected or the amount of recovery after treatment. This method offers a quick and reproducible means of detecting DNA damage and repair in human T-lymphocytes.


Subject(s)
DNA Damage , DNA Repair , Lymphocytes/drug effects , Methyl Methanesulfonate/pharmacology , Cell Division , Cell Line , Cell Separation/methods , Cells, Cultured , DNA Replication , Freezing , Humans , Hydrogen-Ion Concentration , Interleukin-2/pharmacology , Tissue Preservation
15.
Cancer Res ; 48(16): 4529-34, 1988 Aug 15.
Article in English | MEDLINE | ID: mdl-3396005

ABSTRACT

Experiments were designed to measure the effect of folic acid deficiency on a major determinant of cancer lethality, the propensity to form metastases. Murine B16 melanoma cells (F10 strain) were grown in folate-deficient and -supplemented media. After 3 days, cells in the deficient medium had restricted proliferative capacity, low folate levels by bioassay, increased cell volume, abnormal deoxyuridine suppression tests, accumulation of cells in S phase by flow cytometry, and increased numbers of DNA strand breaks. These folate-deficient cells consistently initiated more pulmonary metastases than control cells when injected into host mice. Cell size did not appear to be a major factor in pulmonary metastasis formation. In vitro growth rates and cloning efficiencies were comparable for cells in both types of medium as was subcutaneous growth of tumors. We conclude that folate deficiency increases the metastatic potential of cultured melanoma cells.


Subject(s)
Folic Acid Deficiency/pathology , Neoplasm Metastasis/pathology , Animals , Cell Cycle , Chromosome Aberrations , DNA/biosynthesis , DNA Damage , Melanoma, Experimental/pathology , Mice
16.
J Neurol Sci ; 79(1-2): 189-203, 1987 Jun.
Article in English | MEDLINE | ID: mdl-3112312

ABSTRACT

We studied survival and DNA repair capacity in cultured sporadic ALS and control skin fibroblasts after treatment with DNA damaging agents producing different types of lesions. Mean survival in ALS and control fibroblasts was similar after exposure to ultraviolet (UV) light, x-rays and mitomycin C (MMC). Both mean survival and mean unscheduled (repair) DNA synthesis (UDS) were significantly reduced in ALS fibroblasts following treatment with the alkylating agent methyl methane sulfonate (MMS). These data suggest that ALS cells are relatively deficient in the repair of alkylation damage, possibly of apurinic/apyrimidinic sites, and that they are not unduly sensitive to DNA damage produced by UV light, x-rays and MMC. Normal survival and UDS seen in some patients' cells after MMS treatment indicate a spectrum of repair efficiency, and suggest heterogeneity of the biochemical defect in ALS.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , DNA Repair , Adult , Aged , Cell Survival , Cells, Cultured , DNA/biosynthesis , DNA/drug effects , DNA/radiation effects , DNA Repair/radiation effects , Fibroblasts/metabolism , Fibroblasts/radiation effects , Humans , Methyl Methanesulfonate/pharmacology , Middle Aged , Mitomycin , Mitomycins/pharmacology , Ultraviolet Rays , X-Rays
17.
Ann Neurol ; 21(3): 250-8, 1987 Mar.
Article in English | MEDLINE | ID: mdl-3606032

ABSTRACT

The most common cause of senile and presenile dementia is Alzheimer's disease, a disorder with an undetermined cause. A number of studies have indicated that neurons from patients with Alzheimer's disease have decreased ribonucleic acid levels and reduced protein synthesis. Recent studies using lymphoblasts from patients with Alzheimer's disease have indicated that these cells are more sensitive to deoxyribonucleic acid (DNA)-alkylating agents. We have used cell survival, unscheduled DNA synthesis, and alkaline elution to assess the capacity for DNA repair in skin fibroblasts from normal control subjects, control subjects with central nervous system disease, and patients with Alzheimer's disease. Our results indicate that the Alzheimer's disease cells, unlike normal cells, fail to repair methylmethane sulfonate-induced DNA damage. Both normal and Alzheimer's disease cells are able to ameliorate the effects of ultraviolet light. These results indicate that a specific pathway for DNA repair is affected in Alzheimer's disease. The repair defect may be related to the cause of the disease or may be the cause of the disease.


Subject(s)
Alzheimer Disease/metabolism , DNA Repair , Adolescent , Adult , Aged , Aging/metabolism , Cell Line , Cell Survival , Child , Culture Techniques , DNA/biosynthesis , Female , Fibroblasts/metabolism , Humans , Male , Middle Aged , Reference Values , Skin/metabolism
20.
J Neurol Sci ; 64(1): 11-20, 1984 Apr.
Article in English | MEDLINE | ID: mdl-6234379

ABSTRACT

DNA plays an essential role not only in dividing cells, but also in postmitotic cells such as neurons. Accumulated damage to the nuclear DNA will result in damage to neuronal metabolism. There is suggestive evidence of altered DNA in ALS, Alzheimer's and Parkinson's diseases, and of deficiency of DNA repair mechanisms in these age-related neuronal degenerations and in Huntington's disease. We suggest that these DNA abnormalities are more likely to be the cause of the diseases, rather than an effect of the disease process.


Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Basal Ganglia Diseases/metabolism , DNA/metabolism , Alzheimer Disease/metabolism , Amyotrophic Lateral Sclerosis/etiology , Basal Ganglia Diseases/etiology , Carcinogens/metabolism , Chemical Phenomena , Chemistry , Cross-Linking Reagents/pharmacology , DNA/radiation effects , DNA Repair , Humans , Huntington Disease/metabolism , Parkinson Disease/metabolism
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