True extended haplotypes of p53: indicators of breast cancer risk.
Explore the source record for details and available documents.
Breast Neoplasms↗
Biomedical subjects
M S Wolff
Publications and source records attributed to M S Wolff.
Plasma organochlorine levels and the risk of breast cancer.
BACKGROUND: Exposure to "environmental estrogens" such as organochlorines in pesticides and industrial chemicals has been proposed as a cause of increasing rates of breast cancer. Several studies have reported higher blood levels of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) and polychlorinated biphenyls (PCBs) in patients with breast cancer than in controls. METHODS: We measured plasma levels of DDE and PCBs prospectively among 240 women who gave a blood sample in 1989 or 1990 and who were subsequently given a diagnosis of breast cancer before June 1, 1992. We compared these levels with those measured in matched control women in whom breast cancer did not develop. Data on DDE were available for 236 pairs, and data on PCBs were available for 230 pairs. RESULTS: The median level of DDE was lower among case patients than among controls (4.71 vs. 5.35 parts per billion, P=0.14), as was the median level of PCBs (4.49 vs. 4.68 parts per billion, P=0.72). The multivariate relative risk of breast cancer for women in the highest quintile of exposure as compared with women in the lowest quintile was 0.72 for DDE (95 percent confidence interval, 0.37 to 1.40) and 0.66 for PCBs (95 percent confidence interval, 0.32 to 1.37). Exposure to high levels of both DDE and PCBs was associated with a nonsignificantly lower risk of breast cancer (relative risk for women in the highest quintiles of both DDE and PCBs as compared with women in the lowest, 0.43; 95 percent confidence interval, 0.13 to 1.44). CONCLUSIONS: Our data do not support the hypothesis that exposure to DDT and PCBs increases the risk of breast cancer.
Adult↗
A murine model of genetic susceptibility to lead bioaccumulation.
Previous reports have shown that blood lead levels in humans are associated with a polymorphic form of delta-aminolevulinate dehydratase (ALAD), an enzyme of heme biosynthesis that binds and is inhibited by lead. We hypothesized that ALAD levels may influence the distribution and accumulation of lead in the blood and target organs. To assess this, we studied strains of mice that differ in the numbers of copies of the ALAD gene. Our findings showed that mice with a duplication of the ALAD gene (DBA) accumulated twice the amount of lead in their blood and had higher lead levels in kidney and liver than mice with a single copy of the gene (C57) exposed to the same oral doses of lead during adulthood. Hybrid animals showed intermediate blood lead levels. Levels of blood zinc protoporphyrin (ZPP) increased with lead exposure in C57 animals while they were not affected in DBA mice, suggesting protection from production of this abnormal enzyme in mice with a duplication of the gene. Except for these protective effects in the formation of ZPP in DBA animals, duplication of the ALAD gene was found to increase lead accumulation. We conclude that although these mouse strains do not precisely replicate the polymorphism observed in humans, they may be used as a model to study genetic influences in lead bioaccumulation. Understanding genetic factors that affect susceptibility to lead-induced intoxication could have important implications for public health and intervention initiatives. These mouse strains may represent a useful model for future study of the role of ALAD in lead intoxication.
Administration, Oral↗
Blood levels of DDT and breast cancer risk among women living in the north of Vietnam.
A positive association has been reported between elevated tissue organochlorines (p,p'-DDT/p,p'-DDE, PCBs, dioxins) and breast cancer in some case-control studies and occupational cohort studies. We previously reported high serum levels of p,p'-DDT and its metabolite p,p'-DDE in women living throughout Vietnam. We report here the results of a small hospital-based case-control study examining the association between blood levels of p,p'-DDT/p,p'-DDE and the risk of invasive breast cancer among residents of the north of Vietnam-an area where insecticides such as p,p'-DDT have been heavily used in the recent past. The study was conducted among patients admitted to a single hospital in the capital city of Hanoi in 1994. Study subjects were 21 women newly diagnosed with invasive adenocarcinoma of the breast, who served as cases, and 21 women of similar age with fibrocystic breast disease, who served as controls. No increase was evident in the relative risk of breast cancer with increasing tertiles of serum concentration of the compounds of interest, even after adjustment for major potential confounders, such as age at menarche, parity, history of lactation, and body weight. These results suggest that recent and past exposure to p,p'-DDT does not play an important role in the etiology of breast cancer among women living in a country with a tropical climate where insecticide use for mosquito control is common.
Adult↗
Proposed PCB congener groupings for epidemiological studies.
Explore the source record for details and available documents.
Body Burden↗
Breast cancer risk and environmental exposures.
Although environmental contaminants have potential to affect breast cancer risk, explicit environmental links to this disease are limited. The most well-defined environmental risk factors are radiation exposure and alcohol ingestion. Diet is clearly related to the increased incidence of breast cancer in developed countries, but its precise role is not yet established. Recent studies have implicated exposure to organochlorines including DDT as a risk factor for breast cancer in the United States, Finland, Mexico, and Canada. Other investigations have discovered associations between breast cancer risk and exposures to chemical emissions and some occupational exposures. Several points must be considered in evaluating the relationship of environmental exposure to breast cancer. Among these considerations are the mechanism of tumorigenesis, timing of environmental exposure, and genetic modulation of exposure. Epidemiologic and ecologic investigations must take into account the very complex etiology of breast cancer and the knowledge that tumorigenesis can arise from different mechanisms. Thus crucial exposures as well as reproductive events related to breast cancer may occur years before a tumor is evident. Moreover, environmental contaminants may alter reproductive development, directly or indirectly, and thereby effect the course of tumorigenesis. Such alterations include change in gender, change in onset of puberty, and inhibition or promotion of tumor formation. Timing of exposure is therefore important with respect to mechanism and susceptibility. Finally, genetic polymorphisms exist in genes that govern capacity to metabolize environmental contaminants. Higher risk may occur among persons whose enzymes either are more active in the production of procarcinogens or fail to detoxify carcinogenic intermediates formed from chemicals in the environment.
Breast Neoplasms↗
p53 haplotype determination in breast cancer.
Inheritance of certain germ line haplotypes consisting of three biallelic polymorphisms of p53 has been proposed as a risk factor for breast cancer and colorectal cancer [A. Själander et al., Carcinogenesis (Lond.), 17: 1313-1316, 1996, and Carcinogenesis (Lond.), 16: 1461-1464, 1995]. In their studies, pairwise haplotypes of these three polymorphisms were estimated. Extended haplotypes were further projected from the pairwise combinations. To overcome the necessity to estimate pairwise and extended haplotype frequencies, a PCR method has been developed to determine the absolute extended p53 haplotypes in diploid genomes. The method requires allele-specific PCR, confirmed by restriction analysis, and successive amplicon analysis. It has been applied to a nested case-control study of breast cancer (284 subjects; 99 cases and 185 controls; 182 Caucasians, 56 Hispanics, and 46 African-Americans). Evidence is presented that minor variants of the intron 3, codon 72, and intron 6 polymorphisms were moderately elevated in Caucasian breast cancer cases (intron 3, P = 0.03 for genotype and P = 0.01 for allelic frequency; codon 72, P = 0.07 for genotype and P = 0.054 for allelic frequency; and intron 6, P = 0.02 for genotype and P = 0.02 for allele frequency). Accordingly, analysis of haplotype distributions suggested an association of minor p53 haplotypes with breast cancer risk in Caucasians (P = 0.07). The relative allelic frequencies in breast cancer cases compared with controls also differed by age and menopausal status; the 1-2-1 haplotype was overrepresented in postmenopausal cases (P = 0.02) and cases older than 50 years (P = 0.02), whereas the other minor haplotypes (1-1-2 and rare variants) were overrepresented in premenopausal cases (P = 0.003) and cases 50 years of age and younger (P = 0.02). Genotype distributions at each locus and for all control groups were consistent with Hardy-Weinberg equilibria. Differences in haplotype distribution were associated with ethnicity (Caucasians versus African-Americans and Caucasians versus Hispanics, P < 0.001). The new haplotyping method may be useful in the study of gene-environment interactions.
Adult↗
Temporal variation in chlorinated hydrocarbons in healthy women.
Chlorinated hydrocarbons may increase breast cancer risk. Most epidemiological studies addressing this possibility have used one biological sample to measure a subject's cumulative exposure to these compounds. Little is known about short-term temporal variation in organochlorines, particularly in individuals with low levels. Thus, the reliability of using one sample to assess blood levels of chlorinated hydrocarbons in an epidemiological study is unknown. To better understand the temporal changes in blood measures among women with nonoccupational exposures to these compounds, we collected two 5-ml blood samples, an average of 2 months apart, from each of 31 nonfasting healthy women, ages 45-81 years. Samples were assayed for 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), polychlorinated biphenyls (PCBs), and trans-nonachlor in blinded, matched pairs. Results were adjusted for estimated total plasma lipids. The correlations between the two blood samples were high for DDE and PCBs (lipid-adjusted, r = 0.96 and r = 0.89, respectively). For trans-nonachlor, the correlation was relatively poor (lipid-adjusted r = 0.57); however, with the removal of one outlier, the correlation improved substantially (lipid-adjusted, r = 0.90). The mean difference between the two blood samples in unadjusted [-0.36 ng/ml, 95% confidence interval (CI), -0.97, 0.24 ng/ml, P = 0.23] and lipid-adjusted (-0.035 microgram/g lipid; 95% CI, -0.124, 0.055; P = 0.44) DDE levels was small. Similarly, there was little change in the mean difference for unadjusted (-0.14 ng/ml; 95% CI, -0.53, 0.25 ng/ml; P = 0.47) and lipid-adjusted (0.006 microgram/g lipid; 95% CI, -0.050, 0.062; P = 0.82) PCB levels. The mean differences in trans-nonachlor levels between the two blood draws were also small: unadjusted (-0.03 ng/ml; 95% CI, -0.07, 0.02 ng/ml; P = 0.20) and lipid-adjusted (-0.003 microgram/g lipid; 95% CI, -0.010, 0.004; P = 0.33). These data suggest that temporal changes in organochlorine levels within a 1 to 3-month period are minimal for noncancer patients and that a single measure for estimating exposure is highly reliable for DDE and PCB. For trans-nonachlor, however, where the correlation between blood draws was lower, three samples would be needed for estimating exposure; if an outlier is removed from our data, however, then we can conclude that only a single measure is sufficient. These data, therefore, offer no clear conclusion for the use of a single measurement for trans-nonachlor.
Aged↗
Reduced aliquot size for a plasma organochlorine assay for use in epidemiological studies.
Because archived blood specimens are an important but limited resource for conducting epidemiological studies using biomarkers, it is important to develop analytical techniques that minimize the amount of sample needed. We modified an established 1.0-ml blood plasma organochlorine assay to use smaller volumes. We assessed its utility by comparing the accuracy and precision of measurements obtained with different-sized aliquots of spiked plasma from three pools of known concentration of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) and polychlorinated biphenyls (PCBs; low, medium, and high). There was a modest sacrifice in accuracy using 0.5 as opposed to 1.0 ml. However, the within-batch coefficients of variation, a measure of laboratory error, were consistently low when 0.5-ml aliquots were used. For both DDE and PCB concentrations, this error was less than 5% for the medium and high pools [5-20 parts per billion (ng/ml)] and less than 9% for the low pool (< 1 part per billion). After determining that aliquots of 0.5 ml were sufficient, we performed a blinded quality control analysis of stored plasma. In this study, the within-subject variation was low for DDE and PCBs and substantially lower than the between-subject variation, suggesting that the assay would rank subjects with reasonable precision. Our results suggest that use of 0.5-ml as opposed to 1.0-ml aliquots should not compromise the power of a nested case-control study to detect differences between subjects and would thus save plasma for future research. For populations with very low levels of organochlorines, however, the larger volumes should still be used.
Blood Specimen Collection↗
An evaluation of intraoral lidocaine patches in reducing needle-insertion pain.
Intraoral lidocaine patches have recently been approved by the US Food and Drug Administration for the production of topical anesthesia before superficial dental procedures and for the reduction of pain associated with local anesthetic injections. The results of this 5-center clinical study showed that lidocaine patches were significantly more efficacious than matching placebo patches in reducing the pain associated with 25-gauge needle insertions to the level of bone in the maxillary premolar region. Anesthetic onset occurred within 5 minutes and was present for the entire 15-minute period that the patches were in contact with the oral mucosa. In addition, the patches were safe and well tolerated by study participants. Other potential clinical applications of this novel delivery system are also discussed in this article.
Administration, Topical↗
The role of DDE and polychlorinated biphenyl levels in preterm birth.
Maternal serum levels of DDE and polychlorinated biphenyls (PCB) and their congeners were compared for 20 women who had a spontaneous preterm delivery and 20 matched women who had delivered at term at Mount Sinai Medical Center in New York between October 1990 and August 1993. Since no substantial case-control differences were evident, these findings do not indicate that increased DDE or PCB levels are associated with spontaneous preterm birth.
Adult↗
Breast cancer and environmental risk factors: epidemiological and experimental findings.
Breast cancer has long been associated with reproductive hormone exposures. Recently, greater attention has been focused on environmental exposures that may be responsible for some proportion of breast cancer incidence. Several etiologic aspects are discussed. A number of chemicals induce breast cancer in rodents--including solvents, pesticides, and polycyclic aromatic hydrocarbons--and these might serve as leads for studies in humans. In women, strong links have been established between breast cancer risk and ionizing radiation. Evidence for nonionizing radiation (electromagnetic field) exposures and breast cancer is suggestive, albeit limited. Occupational exposures have not been identified as breast cancer risks, but several associations need further study, including solvents and pesticides. Time of life when exposures take place is important, and this claim is strongly supported by data on cigarette smoking and radiation. Also, basic research has demonstrated that mammary tissue is more susceptible to carcinogenesis at certain periods of breast development. Likewise, prenatal, neonatal, and adolescent exposures deserve continuing attention. Research on etiology of breast cancer should measure environmental exposures and take into account the time of life at which these occur. Complex interactions between exogenous and endogenous carcinogenic agents need further focus, as modulated by varying genetically determined individual susceptibilities.
Animals↗
Analgesic efficacy and safety of an intraoral lidocaine patch.
The effectiveness of intraoral II-docaine patches was tested by asking participants to rate the pain experienced after insertions of a 25-gauge needle. Needlesticks were performed at baseline and at various time points after patch placement. Each needlestick included contact with the periosteum. Lidocaine patches achieved significantly better analgesia than the placebo within 2.5 to five minutes after placement. Drug-related side effects were minimal and venous blood levels of lidocaine were low, averaging 10 to 14 times less than those achieved with a typical injection of lidocaine plus epinephrine. The authors conclude that the lidocaine patches used in this study are effective and safe in reducing needle insertion pain in adults.
Administration, Topical↗
Treatment for breast cancer and blood levels of chlorinated hydrocarbons.
Small studies have examined, with conflicting results, whether breast cancer risk is increased among women exposed to high levels of chlorinated hydrocarbons, as measured in breast fat tissue or peripheral blood collected prior to treatment (pretreatment blood). For a population-based, case-control study, collection of pretreatment blood is a labor-intensive effort. An alternative is to collect blood from cases at interview, as is done for controls, after breast cancer treatment has commenced (posttreatment blood). It is unknown whether treatment affects blood levels of the organochlorines 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) or polychlorinated biphenyls (PCBs). The purpose of this study was to determine whether pretreatment versus posttreatment blood samples yielded significantly different estimates of cumulative exposure to DDE and PCBs among newly diagnosed breast cancer patients. Two-ml blood samples were collected prior to and after treatment for breast cancer from 22 nonfasting women, ages 45-87 years, newly diagnosed with invasive disease. Treatment was defined as major surgery (mastectomy or node removal), radiation, hormones (tamoxifen), or chemotherapy. Pretreatment and posttreatment blood samples were assayed for DDE and PCBs in blinded, matched pairs. The reported concentrations (volume basis) were adjusted for estimated total plasma lipids. For DDE, mean differences in unadjusted [0.99 ng/ml; 95% confidence interval (CI), -0.36 to 2.34 ng/ml] and lipid-adjusted (0.05 microgram/g lipid; 95% CI, -0.04 to 0.13 microgram/g lipid) levels were small. For PCBs, the unadjusted (0.68 ng/ml; 95% CI, 0.05 to 1.30 ng/ml) and adjusted (0.070 microgram/g lipid; 95% CI, -0.009 to 0.149 microgram/g lipid) mean differences were of borderline statistical significance. The mean percent change in lipid-adjusted organochlorine levels did not vary substantially between treatment groups, except for those patients receiving chemotherapy [n = 5; 15.8% (DDE), 29.4% (PCBs)]. Adjusted mean differences also increased with increasing time between the pretreatment and posttreatment blood draws. In multiple regression models that included treatment, age, race, stage, and time between blood draws, only chemotherapy appeared to predict the percent change in adjusted pretreatment and posttreatment levels of DDE or PCBs (P = 0.10 and 0.06, respectively). Posttreatment blood samples drawn within 3 months of pretreatment samples, with the exception of those drawn after the commencement of chemotherapy, provide similar measures of DDE body burden levels among breast cancer cases. The use of blood samples collected after treatment, rather than before treatment, for characterizing PCB levels may lead to misclassification of exposure.
Aged↗
Environmental estrogens.
Explore the source record for details and available documents.
Breast Neoplasms↗
Pesticides--how research has succeeded and failed in informing policy: DDT and the link with breast cancer.
Investigation of chemical exposures as possible etiologic factors for breast cancer has not been a research priority in the United States, which is surprising given the evidence from animal studies that environmental chemicals cause cancer and reproductive dysfunction. Study of environmental chemicals has also been indicated by the failure of traditional epidemiologic methods to account for significant proportions of breast cancer incidence with other risk factors. The fact that breast cancer risk is strongly associated with reproductive hormones is a further clue that environmental chemicals should be investigated. In addition to cancer, specific outcomes that need to be explored are reproductive dysfunction, immunotoxicity and neurotoxicity. Policy guiding our research should encourage toxicologic investigations of exposures to environmental chemicals that use state-of-the-art methods to determine exposure and human health effects. Using the approach suggested by John McLachlan, functional toxicology should be used to assess the activity of chemicals with regard to these outcomes. Just as dioxin toxicity can be expressed as toxic equivalents, estrogenic activity, for example, can be characterized in terms of estrogenic equivalents. In addition to the need to undertake this kind of research, needs for methods development and creative research funding mechanisms are discussed. Prevention of breast cancer may require intervention at an early age. Better understanding of breast cancer etiology, and especially its environmental components, may lead us toward that goal.
Breast Neoplasms↗
Environmental organochlorine exposure as a potential etiologic factor in breast cancer.
Known risk factors for breast cancer do not account for a significant proportion of the overall incidence. Reproductive factors and endogenous hormones are thought to be responsible for a large component of risk. An environmental contribution has been sought in the past to explain the international trends in breast cancer rates and changes in risk among migrating populations. Recently, environmental research has turned to investigation of exogenous chemical exposures, including environmental contamination, as potential risk factors that may arise from the hormonal activity or from the carcinogenicity of many of these chemicals. Several reports since 1991 suggest that organochlorines may be a risk factor for breast cancer. The data are strongest for DDT. For PCBs, the results to date have been equivocal if not entirely negative. However, different groups of polychlorinated biphenyl (PCB) congeners are known to provoke biological responses that are structure specific. A wide divergence of estrogenic response, cytochrome P450 activity, and biological half-life exists within these groups of PCB congeners. Therefore, understanding breast cancer risk from PCB exposure requires attention to congener structures in complex mixtures and to temporal changes in exposure. Investigation of environmental contributions to breast cancer risk offers the potential for understanding more about the etiology of this complex disease and may also provide opportunities for prevention of the most common cancer among women in the United States.
Breast Neoplasms↗
Occlusion: the foundation of restorative dentistry an interview with Dr. Mark S. Wolff. Interview by Phillip Bonner.
Explore the source record for details and available documents.
Ceramics↗