Towards a fuller assessment of the economic benefits of reducing air pollution from fossil fuel combustion: Per-case monetary estimates for children's health outcomes.

BACKGROUND: Impacts on children's health are under-represented in benefits assessments of policies related to ambient air quality and climate change. To complement our previous compilation of concentration-response (C-R) functions for a number of children's health outcomes associated with air pollution, we provide per-case monetary estimates of the same health outcomes. OBJECTIVES: Our goal was to establish per-case monetary estimates for a suite of prevalent children's health outcomes (preterm birth, low birth weight, asthma, autism spectrum disorder, attention-deficit/hyperactivity disorder, and IQ reduction) that can be incorporated into benefits assessments of air pollution regulations and climate change mitigation policies. METHODS: We conducted a systematic review of the literature published between January 1, 2000 and June 30, 2018 to identify relevant economic costs for these six adverse health outcomes in children. We restricted our literature search to studies published in the U.S., with a supplemental consideration of studies from the U.K. and prioritized literature reviews with summary cost estimates and papers that provided lifetime cost of illness estimates. RESULTS: Our literature search and evaluation process reviewed 1065 papers and identified 12 most relevant papers on per-case monetary estimates for preterm birth, low birth weight, asthma, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Details are presented in full. We separately identified estimates of the lost lifetime earnings associated with the loss of a single IQ point. The final per-case cost estimates for each outcome were selected based on the most robust evidence. These estimates range from $23,573 for childhood asthma not persisting into adulthood to $3,109,096 for a case of autism with a concurrent intellectual disability. CONCLUSION: To our knowledge, this is the first time that the child-specific health outcomes of preterm birth, low birth weight, asthma, autism spectrum disorder, attention-deficit/hyperactivity disorder, and IQ reduction have been systematically valued and presented in one place. This is an important addition to the body of health-related valuation literature as these outcomes have substantial economic costs that are not considered in most assessments of the benefits of air pollution and climate mitigation policies. In general, however, the available per-case estimates presented here did not incorporate the broad societal and long-term costs and are likely underestimates. Although our context has been air pollution and climate policies, the per-case monetary estimates presented here can be applied to other environmental exposures. Fuller assessments of health benefits to children and their corresponding economic gains will improve decision-making on environmental policy.

Towards a fuller assessment of benefits to children's health of reducing air pollution and mitigating climate change due to fossil fuel combustion.

BACKGROUND: Fossil fuel combustion by-products, including particulate matter (PM2.5), polycyclic aromatic hydrocarbons (PAH), nitrogen dioxide (NO2) and carbon dioxide (CO2), are a significant threat to children's health and equality. Various policies to reduce emissions have been implemented to reduce air pollution and mitigate climate change, with sizeable estimated health and economic benefits. However, only a few adverse outcomes in children have been considered, resulting in an undercounting of the benefits to this vulnerable population. OBJECTIVES: Our goal was to expand the suite of child health outcomes addressed by programs to assess health and economic benefits, such as the Environmental Protection Agency (EPA) Benefits Mapping and Analysis Program (BenMAP), by identifying concentration-response (C-R) functions for six outcomes related to PM2.5, NO2, PAH, and/or PM10: preterm birth (PTB), low birthweight (LBW), autism, attention deficit hyperactivity disorder, IQ reduction, and the development of childhood asthma. METHODS: We conducted a systematic review of the literature published between January 1, 2000 and April 30, 2018 to identify relevant peer-reviewed case-control and cohort studies and meta-analyses. In some cases meta-analyses were available that provided reliable C-R functions and we assessed their consistency with subsequent studies. Otherwise, we reviewed all eligible studies published between our search dates. RESULTS: For each pollutant and health outcome, we present the characteristics of each selected study. We distinguish between C-R functions for endpoints having a causal or likely relationship (PTB, LBW, autism, asthma development) with the pollutants for incorporation into primary analyses and endpoints having a suggestive causal relationship with the pollutants (IQ reduction, ADHD) for secondary analyses. CONCLUSION: We have identified C-R functions for a number of adverse health outcomes in children associated with air pollutants largely from fossil fuel combustion. Their incorporation into expanded assessments of health benefits of clean air and climate mitigation policies will provide an important incentive for preventive action.

Prenatal exposure to fine particles and polycyclic aromatic hydrocarbons and birth outcomes: a two-pollutant approach.

BACKGROUND: Previous epidemiologic studies have considered the effects of individual air pollutants on birth outcomes, whereas a multiple-pollutant approach is more relevant to public health policy. OBJECTIVES: The present study compared the observed effect sizes of prenatal fine particulate matter (PM2.5) and polycyclic aromatic hydrocarbons (PAH) (a component of PM2.5) exposures on birth outcome deficits, assessed by the single vs. two-pollutant approaches. METHODS: The study sample included 455 term infants born in Krakow to non-smoking mothers, among whom personal exposures to PM2.5 and PAH were monitored in the second trimester of pregnancy. The exposure effect estimates (unstandardized and standardized regression coefficients) on birth outcomes were determined using multivariable linear regression models, accounting for relevant covariates. RESULTS: In the single-pollutant approach, each pollutant was inversely associated with all birth outcomes. The effect size of prenatal PAH exposure on birth weight and length was twice that of PM2.5, in terms of standardized coefficients. In the two-pollutant approach, the negative effect of PM2.5 on birth weight and length, adjusted for PAH exposure, lost its significance. The standardized effect of PAH on birth weight was 10-fold stronger (ß = -0.20, p = 0.004) than that estimated for PM2.5 (ß = -0.02, p = 0.757). CONCLUSION: The results provide evidence that PAH had a greater impact on several measures of fetal development, especially birth weight, than PM2.5. Though in the single-pollutant models PM2.5 had a significant impact on birth outcomes, this effect appears to be mediated by PAH.

Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity.

BACKGROUND/OBJECTIVES: Cesarean section (CS) and antibiotic use during pregnancy may alter normal maternal-offspring microbiota exchange, thereby contributing to aberrant microbial colonization of the infant gut and increased susceptibility to obesity later in life. We hypothesized that (i) maternal use of antibiotics in the second or third trimester of pregnancy and (ii) CS are independently associated with higher risk of childhood obesity in the offspring. SUBJECTS/METHODS: Of the 727 mothers enrolled in the Northern Manhattan Mothers and Children Study, we analyzed the 436 mother-child dyads followed until 7 years of age with complete data. We ascertained prenatal antibiotic use by a questionnaire administered late in the third trimester, and delivery mode by medical record. We derived age- and sex-specific body mass index (BMI) z-scores using the CDC SAS Macro, and defined obesity as BMI z⩾95th percentile. We used binary regression with robust variance and linear regression models adjusted for maternal age, ethnicity, pre-gravid BMI, maternal receipt of public assistance, birth weight, sex, breastfeeding in the first year and gestational antibiotics or delivery mode. RESULTS: Compared with children not exposed to antibiotics during the second or third trimester, those exposed had 84% (33-154%) higher risk of obesity, after multivariable adjustment. Second or third trimester antibiotic exposure was also positively associated with BMI z-scores, waist circumference and % body fat (all P<0.05). Independent of prenatal antibiotic usage, CS was associated with 46% (8-98%) higher offspring risk of childhood obesity. Associations were similar for elective and non-elective CS. CONCLUSIONS: In our cohort, CS and exposure to antibiotics in the second or third trimester were associated with higher offspring risk of childhood obesity. Future studies that address the limitations of our study are warranted to determine if prenatal antibiotic use is associated with offspring obesity. Research is also needed to determine if alterations in neonatal gut microbiota underlie the observed associations.

Effects of prenatal polycyclic aromatic hydrocarbon exposure and environmental tobacco smoke on child IQ in a Chinese cohort.

OBJECTIVE: This study of a birth cohort in the city of Tongliang in Chongqing, China, evaluated the relationship between two prenatal exposures (polycyclic aromatic hydrocarbons(PAH) and environmental tobacco smoke(ETS)) and child intelligence quotient (IQ) as measured by the Wechsler Preschool and Primary Scale of Intelligence at age 5 years. A coal-fired power plant was the major source of ambient PAH in this city. We tested the hypothesis that, after adjusting for potential confounders, prenatal exposure to these pollutants would be associated with lower IQ scores at 5 years of age. METHODS: Nonsmoking mothers and children were enrolled before delivery. PAH exposure was measured by DNA adducts in umbilical cord white blood cells using High-Performance Liquid Chromatography-Fluorescence. Estimated exposure to environmental tobacco smoke was based on personal interview. At age 5 years, scores for verbal, performance, and full scale IQ were obtained. Multiple regression was used to test the main effects of adducts and environmental tobacco smoke on IQ and to explore the interactions between these exposures on IQ. RESULTS: after adjusting for potential confounders, neither DNA adducts nor exposure to environmental tobacco smoke had significant main effects on IQ. However, significant interactions between adducts and environmental tobacco smoke were observed on full scale (p=0.025) and verbal (p=0.029) IQ scores, indicating that the adverse effects of prenatal PAH exposure became greater as exposure to environmental tobacco smoke increased. The interaction on performance IQ score was not significant (p=0.135). CONCLUSION: These results suggest that exposure of pregnant women to emissions of PAHs from the coal-burning plant, in combination with prenatal exposure to envrionmental tobacco smoke, may have adversely affected cognitive function of children at age 5. The polluting coal-fired plant has since been closed by the government, with likely important benefits to child health and development.

A systematic review of axillary nodal irradiation for the management of the axilla in patients with early-stage breast cancer.

BACKGROUND: Given numerous publications and clinical trials regarding axillary management in breast cancer, we sought to summarize this complex literature to help clarify this field for clinicians. This systematic review focuses on the role of irradiation of the axillary nodes (locoregional nodal irradiation [LRNI]) in the management of the axilla in patients with early-stage breast cancer in various clinical settings. METHODS: We searched MEDLINE and EMBASE databases, the Cochrane library, the proceedings of the ASCO, the ASTRO, the ESMO, the ESTRO, and the San Antonio Breast Cancer Symposium (2016-2019) meetings. The quality of the studies was assessed with design-specific tools. The study was registered in PROSPERO. RESULTS: We included one systematic review, one individual patient data (IPD) meta-analysis, and five randomized controlled trials (RCTs). After axillary lymph node dissection (ALND), LRNI resulted in small benefits in breast cancer specific mortality, locoregional recurrence, and distant metastases-free survival but not overall survival. After a positive sentinel node biopsy (SLNB), LRNI may provide equivalent locoregional control and disease-free survival (DFS) compared to ALND with a lower risk of lymphedema. No randomized data is available for the neoadjuvant setting. CONCLUSIONS: The summary of the role of radiation, is relevant to radiation oncologists for choosing the correct cohort of patient requiring LRNI and to surgeons making clinical decisions regarding the timing and type of breast reconstruction offered to patients.

Environment and cancer: who are susceptible?

Acting in concert with individual susceptibility, environmental factors such as smoking, diet, and pollutants play a role in most human cancer. However, new molecular evidence indicates that specific groups-characterized by predisposing genetic traits or ethnicity, the very young, and women-may have heightened risk from certain exposures. This is illustrated by molecular epidemiologic studies of environmental carcinogens such as polycyclic aromatic hydrocarbons and aromatic amines. Individual genetic screening for rare high-risk traits or for more common, low-penetrant susceptibility genes is problematic and not routinely recommended. However, knowledge of the full spectrum of both genetic and acquired susceptibility in the population will be instrumental in developing health and regulatory policies that increase protection of the more susceptible groups from risks of environmental carcinogens. This will necessitate revision of current risk assessment methodologies to explicitly account for individual variation in susceptibility to environmental carcinogens.

Formaldehyde: a question of cancer policy?

This article describes recent events concerning the assessment and regulation of formaldehyde, and evaluates the scientific data pertaining to the carcinogenicity of this substance in the context of established cancer policies and guidelines. The conclusion is that recent decisions by several federal agencies to defer action to limit human exposure to formaldehyde may be a "test case" for a new, less protective policy concerning the regulation of carcinogenic substances in general.

Molecular cancer epidemiology: a new tool in cancer prevention.

Molecular epidemiology is a promising new tool in the study of environmental carcinogenesis and, particularly, in cancer prevention. Genetic damage and mutation are believed to play a critical role in chemical carcinogenesis. By incorporating biologic markers of dose or response to carcinogens (such as mutagenicity of body fluids, carcinogen-DNA adducts, chromosomal abnormalities, and somatic cell mutation) into human bio-monitoring or molecular epidemiologic studies, one can detect potential hazards early and increase the power of studies to determine causal relationships. Such markers can also improve extrapolation of risks from experimental animals to humans or from one human population to another. During the past 5 years, there has been considerable progress in developing markers and applying them in human (largely pilot) studies. A review of this experience--with particular emphasis on carcinogen-DNA adducts--affords a better awareness both of the significance of biologic markers and the research needed to fill gaps in understanding. Criteria for marker validation and sound study design are presented that should greatly enhance future research.

Molecular epidemiology: on the path to prevention?

Cancer prevention has been the stated goal of molecular cancer epidemiology for the past 17 years. In this review, progress toward that goal is evaluated by using as examples well-studied environmental exposures-i.e., tobacco smoke, polycyclic aromatic hydrocarbons, aflatoxin B(1), benzene, and hepatitis B virus-and their roles in lung, breast, and liver cancers and leukemia. The contributions of molecular epidemiology discussed here include providing evidence that environmental agents pose carcinogenic risks, helping establish the causal roles of environmental factors in cancer, identifying environment-susceptibility interactions and populations at greatest risk, and developing new intervention strategies. Molecular epidemiologic and other data indicate that assessment of carcinogenic risks should address both the range of risk across the population and the risk to subgroups who may be at high risk because of genetic or acquired susceptibilities, including young children. However, for the most part, research results have not yet been effectively translated into risk assessments and preventive health policies. An infrastructure linking scientists, policy makers, and other constituencies is needed to facilitate this process. To extend our knowledge, the second generation of molecular epidemiologic research should include large-scale, collaborative studies incorporating validated biomarkers and automated technologies. An incentive to make the necessary investment is the recognition that prevention of only 20% of cancer in the United States would result in 200000 fewer new cases diagnosed each year and an annual savings of $21.4 billion in direct costs alone.

Molecular epidemiology: insights into cancer susceptibility, risk assessment, and prevention.

Recent molecular epidemiologic research provides compelling new evidence that environmental factors are major contributors to human cancer and that their risks are strongly influenced by genetic and acquired susceptibility. In particular, molecular epidemiology has demonstrated substantial variability in biologic response to carcinogens and suggests that certain groups-such as the very young, those with predisposing genetic traits or nutritional deficits, and even certain ethnic groups-are likely to have greater risk from selected exposures than other members of the population. This work implies that major gains in prevention of cancer, which will claim more than 554 000 American lives this year, will necessitate health and regulatory policies that protect these more susceptible groups and individuals from risks of man-made and naturally occurring environmental carcinogens. The specific implication from this research is that, to be effective in prevention, risk assessments developed in support of these policies by regulatory bodies, such as the Environmental Protection Agency, should reflect the available scientific data on individual variability in both exposure and susceptibility.

Perspectives of comparing risks of environmental carcinogens.

In 1987, investigators (Ames et al.) concluded that the risks of man-made industrial carcinogens and pesticides (outside of the workplace) are trivial compared with the risks of naturally occurring carcinogens found mostly in the diet. They used a ranking system based on human exposure and rodent potency (HERP) data to arrive at this conclusion. As a result, they recommend that regulatory agencies, such as the Environmental Protection Agency and the Food and Drug Administration, base their priorities in this area on their HERP system. We analyzed the assumptions and data set upon which the HERPs were based, concluding that such a simplified approach to set public health policy is inappropriate given the underlying uncertainties. However, we note that when comparisons are consistently based on estimates of average daily exposure to common carcinogens, the HERP scores of many man-made pollutants are comparable to those of naturally occurring carcinogens in the diet.

Biomarkers of environmental tobacco smoke in preschool children and their mothers.

BACKGROUND: Adverse health effects attributable to environmental tobacco smoke (ETS) include respiratory illness and lung cancer in nonsmokers. There is accumulating evidence that children may be at heightened risk of cancer later in life as a result of exposure to carcinogens during their early development. It is of concern that as many as 9 million American children under the age of 5 years may be exposed to ETS. PURPOSE: Our goal was to assess whether levels of cotinine and polycyclic aromatic hydrocarbon-albumin (PAH-albumin) are associated with ETS exposure in children and in women of reproductive age, after accounting for background exposures to PAHs in the diet, workplace, and the home environment. METHODS: The study cohort was composed of 87 Hispanic and African-American mothers and 87 of their preschool children (2-5 years of age). Plasma cotinine was analyzed by gas chromatography; PAH-albumin adducts in peripheral blood were analyzed by enzyme-linked immunosorbent assay. Exposure data were obtained by interview-administered questionnaires. RESULTS: Both cotinine and PAH-albumin were significantly higher in the children whose mothers smoked than in the children of nonsmoking mothers (P < .001 and P < .05, respectively). Among the children of nonsmoking mothers, cotinine levels were also significantly higher in those who had ETS exposure from others in the household compared with the unexposed children. By regression analysis, after adjustment for ethnicity, there was a significant dose-response relationship between cotinine and the number of cigarettes smoked per day by the mother, both in the children (partial r2 = .23; P = .01) and in the mothers (partial r2 = .22; P = .01). Among the nonsmoking mothers, regression of biomarkers against total passive smoking exposure also showed a significant association with cotinine (r2 = .25; P = .04). PAH-albumin did not show the same dose-related response with the smoking variables. Mothers' cotinine levels were significantly correlated with those of their children (r = .76; P < .001) as were PAH-albumin adducts (r = .27; P = .014). CONCLUSION: ETS exposure of young children via their mothers' smoking is associated with increases not only in the internal dose of ETS (cotinine), which has been previously reported, but also in the biologically effective dose of the carcinogenic (PAH) components of ETS (PAH-albumin adducts). This observation underscores the carcinogenic and public health hazard of ETS. IMPLICATIONS: Given the relatively low level of ETS exposure in this study, these results reinforce the need for effective programs aimed at smoking prevention and cessation among women, particularly women of reproductive age and minorities.

DNA adducts, protein adducts, and sister chromatid exchange in cigarette smokers and nonsmokers.

In order to validate markers of internal dose and biologically effective dose of carcinogens, a battery of measurements was made on blood samples from 22 smokers and 24 nonsmokers. The markers included immunoreactivity in an enzyme-linked immunosorbent assay (ELISA) quantified in white blood cells with the use of a polyclonal anti-benzo[a]pyrene diol epoxide-I-DNA antibody, 4-aminobiphenyl hemoglobin (4-ABP-Hb) adducts measured by negative chemical ionization mass spectrometry, sister chromatid exchange (SCE) in cultured lymphocytes, and cotinine in plasma measured by radioimmunoassay. Several blood samples were drawn from each subject. In blood samples 1 and 3 having detectable levels of DNA adducts, mean femtomole-per-microgram levels were consistently higher among smokers compared to nonsmokers. The borderline significance of this difference may be attributable to the small numbers of subjects. Consistently higher adduct levels were seen in females compared to males. In sample 3, adduct levels were significantly correlated with measurements of active smoking in smokers and with passive smoking in nonsmokers. By contrast to the ELISA data, which may reflect cumulative exposure from multiple background sources, the 4-ABP-Hb assay was able to distinguish clearly between smokers and nonsmokers. SCEs were significantly elevated in the smokers compared to nonsmokers. Also observed were significant correlations between 4-ABP-Hb and both cotinine and SCEs, as well as a positive correlation between the 4-ABP-Hb and DNA adduct levels (sample 3) that was highly significant. The correlation between DNA and 4-ABP-Hb adducts was significant in smokers but not nonsmokers (sample 3). These results support the need for batteries of markers to detect and to quantify the carcinogenic dose to humans resulting from both specific and "background" environmental exposures.

Detection of polycyclic aromatic hydrocarbon-DNA adducts in white blood cells of foundry workers.

Iron foundry workers, exposed to high levels of polycyclic aromatic hydrocarbons (PAHs), silica, and metal fumes and dusts, are at elevated risk of lung cancer. Benzo(a)pyrene and a number of structurally related PAHs are metabolically activated to diol epoxides (e.g., 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a) pyrene) which are mutagenic, carcinogenic in experimental animals, and form covalent adducts with DNA. The levels of these adducts were measured in an enzyme-linked immunosorbent assay using a polyclonal anti-benzo(a)pyrene diol epoxide-I-DNA antibody which cross-reacts with DNA modified by diol epoxides of structurally related PAHs. DNA was analyzed from peripheral blood cells of 35 Finnish foundry workers and 10 controls. Workers were classified as having low (less than 0.05 micrograms/m3), medium (0.05-0.2 micrograms/m3), or high (greater than 0.2 micrograms/m3) exposure to benzo(a)pyrene (as an indicator of PAH). When adjustment was made for cigarette smoking and time since vacation, benzo(a)pyrene exposure was significantly related to adduct levels (P = 0.0001). Each of the three exposure groups had significantly elevated adduct levels compared to controls. Among the exposed workers, the low group differed significantly from the high and medium categories. This study supports the usefulness of monitoring adduct formation in a population occupationally exposed to carcinogens.

Immunohistochemical quantitation of polycyclic aromatic hydrocarbon-DNA adducts in human lymphocytes.

The formation of polycyclic aromatic hydrocarbon-DNA adducts was studied in peripheral blood lymphocytes obtained from men with occupational and environmental exposure. Subjects included coke factory workers, residents from the vicinity of the cokery, and rural region inhabitants (16 individuals in each exposure group). Adducts were determined by immunohistochemical analysis using a polyclonal antiserum recognizing benzo(a)pyrene and related polycyclic aromatic hydrocarbon diol epoxide-DNA adducts, a biotinylated secondary antiserum, and streptavidin-conjugated FITC. Propidium iodide was used to quantitate nuclear DNA. Dual fluorescence intensities were simultaneously measured with a Zeiss Axiovert microscope and a Bio-Rad MRC-600 argon laser scanning confocal attachment. Adducts were significantly elevated (P < 0.001) in both occupational and environmental groups, as compared to the rural control group by Mann-Whitney U test. The distribution of the data indicated the existence of cells with relatively higher adduct levels. The percentages of these so called "higher adduct-level cells" were 13.6, 11.5, and 3.7 in cokery workers, environmentally exposed individuals, and rural controls, respectively. The immunohistochemical method allows visualization and relative quantitation of polycyclic aromatic hydrocarbon-DNA adducts in individual lymphocytes. It requires a much smaller amount of blood than the previously used 32P-postlabeling and ELISA methods, which used isolated bulk DNA. It can also be used for adduct quantitation in biopsy material. The results of this pilot study indicate that this technique is a promising addition to biomonitoring studies.

Comparison of DNA adducts and sister chromatid exchange in lung cancer cases and controls.

In a molecular epidemiological study of lung cancer cases (n = 81) and noncancer controls (n = 67), polycyclic aromatic hydrocarbon (PAH)-DNA adducts were evaluated in peripheral blood leukocytes from all subjects and in a smaller number of lung tissue specimens collected prior to or at surgery. Sister chromatid exchanges (SCE) in lymphocytes were also studied in a subset of cases and controls. Questionnaire, medical record, or tumor registry data provided a family history of cancer, as well as information on cigarette smoking, dietary and occupational exposure to PAHs, and other factors related to SCEs. In both cases and controls PAH-DNA adducts in leukocytes measured by an enzyme-linked immunosorbent assay were not significantly related to age, sex, ethnicity, amount of cigarette smoking, passive smoking, dietary charcoal, or caffeine consumption. Nor did family history of cancer or histological type of cancer significantly affect adduct levels. However, when subjects were stratified by smoking status (current, former, and nonsmoker), lung cancer cases who were current smokers had significantly higher levels of covalent adducts than current smoker controls. A seasonal variation was observed in PAH-DNA binding, with a peak in adduct levels during July-October. This peak corresponds to that seen in a prior study of aryl hydrocarbon hydroxylase inducibility by other investigators. The finding of significant levels of PAH-DNA adducts in former smokers and non-smokers supports an earlier observation that this marker is not smoking specific but reflects a pervasive and variable "background" exposure to PAH. These results are consistent with a genetically determined enhancement of PAH-DNA adduct formation in leukocytes of lung cancer cases which is evident in current smokers. The results in lung tissue are limited by the small number of samples. Adduct levels were not significantly increased in lung tissue of smokers compared with nonsmokers. An inverse linear correlation was seen between adduct values in lung tissue and age of the donors. SCEs were significantly related to pack years of smoking. However, there was no difference in the frequency of SCE between cases and controls; nor were SCE and DNA adducts significantly correlated in this small sample.

Multiple biological markers in germ cell tumor patients treated with platinum-based chemotherapy.

Blood samples from 36 germ cell tumor patients receiving chemotherapy with either cisplatin or carboplatin in combination with other drugs [etoposide or vinblastine, cyclophosphamide, dactinomycin, and bleomycin (VAB-6)] were analyzed for the presence of 7 different biological markers. The biomarkers included platinum-protein adducts, platinum-DNA adducts, sister chromatid exchange (SCE), micronuclei (MN), and somatic gene mutation at the hypoxanthine phosphoribosyl transferase (HPRT) locus and the glycophorin A (GPA) loci (NO and NN). Patients were asked to donate 9 serial blood samples: a pretreatment sample followed by another drawn 12-24 h after each of four cycles of treatment and a final sample provided 3-6 months after the last cycle. Most individuals gave 7-8 samples; 7 individuals donated all 9. Because of limited amounts of cells in some cases, it was not possible to carry out all 7 assays on every sample. Pt-protein adducts, Pt-DNA adducts, and SCE showed a direct and consistent effect of treatment and were very highly correlated. A significant correlation was also seen between both Pt-protein and Pt-DNA adducts and HPRT mutation. All of the posttreatment samples were significantly elevated compared to the baseline sample. These markers also remained elevated 3-6 months after the end of treatment. By contrast, MN, HPRT mutation, and GPA mutation (both NO and NN variants) showed varying patterns of dose response, probably reflective of the differing biology of these markers scored in lymphocytes (MN and HPRT) and erythrocytes (GPA). MN were significantly elevated in the posttreatment samples drawn at cycles 2 and 3. Although induction of HPRT mutation was only of marginal significance, results here are for the mutant frequency determination assay only. In progress is the potentially more informative analysis of the type of mutations by Southern blot and the sequencing of mutations to look for characteristic mutational spectra. The GPA assay showed a significant increase over baseline in samples drawn after cycles 3 and 4 (NO variants) and after cycles 2, 3, and 4 (NN variants). The level of GPA mutation (both NO and NN variants) was clearly elevated even 3-6 months after the last cycle of chemotherapy. Correlations were seen between HPRT and MN as well as between GPA NO and GPA NN variants. Analysis of biomarkers by treatment group does not reveal a consistent pattern or trend across all cycles.(ABSTRACT TRUNCATED AT 400 WORDS)

Association between carcinogen-DNA adducts in white blood cells and lung cancer risk in the physicians health study.

In this matched case-control study nested within the prospective Physicians' Health Study, we evaluated whether DNA damage in blood samples collected at enrollment significantly predicted risk, consistent with our hypothesis that cases have greater biological susceptibility to polycyclic aromatic hydrocarbons and other aromatic tobacco carcinogens. The subjects were 89 cases of primary lung cancer and 173 controls, all males, matched on smoking, age, and duration of follow-up. Aromatic-DNA adducts were measured in WBCs by the nuclease P1-enhanced (32)P-postlabeling method that primarily detects smoking-related adducts. Among current smokers, but not former or nonsmokers, there was a significant increase in mean adduct levels of cases compared with controls (11.04 versus 5.63; P = 0.03). "Healthy" current smokers who had elevated levels of aromatic DNA adducts in WBCs were approximately three times more likely to be diagnosed with lung cancer 1-13 years later than current smokers with lower adduct concentrations (odds ratio, 2.98; 95% confidence interval, 1.05-8.42; P = 0.04). We were not able to discern case-control differences in former smokers and nonsmokers. The findings are of interest because they suggest that individuals who become cases have greater biological susceptibility to tobacco carcinogens, a biological difference, which manifests most clearly while exposure is ongoing.

A summary of recent findings on birth outcomes and developmental effects of prenatal ETS, PAH, and pesticide exposures.

Inner-city minority populations are high-risk groups for adverse birth outcomes and also more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), benzo[a]pyrene B[a]P, other ambient polycyclic aromatic hydrocarbons (global PAHs), and residential pesticides. The Columbia Center for Children's Environmental Health (CCCEH) is conducting a prospective cohort study of 700 northern Manhattan pregnant women and newborns to examine the effects of prenatal exposure to these common toxicants on fetal growth, early neurodevelopment, and respiratory health. This paper summarizes results of three published studies demonstrating the effects of prenatal ETS, PAH, and pesticides on birth outcomes and/or neurocognitive development [Perera FP, Rauh V, Whyatt RM, Tsai WY, Bernert JT, Tu YH, et al. Molecular evidence of an interaction between prenatal environment exposures on birth outcomes in a multiethnic population. Environ Health Perspect 2004;12:630-62; Rauh VA, Whyatt RM, Garfinkel R, Andrews H, Hoepner L, Reyes A, et al. Developmental effects of exposure to environmental tobacco smoke and material hardship among inner-city children. Neurotoxicol Teratol 2004;26:373-85; Whyatt RM, Rauh V, Barr DB, Camann DE, Andrews HF, Garfinkel R, et al. Prenatal insecticide exposures, birth weight and length among an urban minority cohort. Environ Health Perspect, in press]. To evaluate the effects of prenatal exposure to ETS, PAHs, and pesticides, researchers analyzed questionnaire data, cord blood plasma (including biomarkers of ETS and pesticide exposure), and B[a]P-DNA adducts (a molecular dosimeter of PAHs). Self-reported ETS was associated with decreased head circumference (P = 0.04), and there was a significant interaction between ETS and adducts such that combined exposure had a significant multiplicative effect on birth weight (P = 0.04) and head circumference (P = 0.01) after adjusting for confounders. A second analysis examined the neurotoxic effects of prenatal ETS exposure and postpartum material hardship (unmet basic needs in the areas of food, housing, and clothing) on 2-year cognitive development. Both exposures depressed cognitive development (P < 0.05), and there was a significant interaction such that children with exposure to both ETS and material hardship exhibited the greatest cognitive deficit (7.1 points). A third analysis found that cord chlorpyrifos, and a combined measure of cord chlorpyrifos, diazinon, and propoxur-metabolite, were inversely associated with birth weight and/or length (P < 0.05). These results underscore the importance of policies that reduce exposure to ETS, air pollution, and pesticides with potentially adverse effects on fetal growth and child neurodevelopment.