The NIOSH Retrospective Pesticide Reference Database.

For the National Institute for Occupational Safety and Health (NIOSH) case-control study of glioma among non-metropolitan residents, pesticide information was considered critical. Responses to open-ended questions about pesticide exposures had to be grouped for analysis. Our aim was to classify pesticide responses in biologically relevant categories. We built the NIOSH Retrospective Pesticide Reference Database (NIOSH-RPRD) on over 1000 pesticide products and chemicals, particularly those likely to be used in the upper Midwest, using multiple sources. We obtained first and last years of product registration and product pesticide ingredients and their relative weights from the U.S. Environmental Protection Agency's Pesticide Product Information System. We added fields for pesticide class (organophosphate, etc.), carcinogenicity ratings, and evidence regarding endocrine-disrupting activity. Participant data were merged with the database, allowing each product recalled by a respondent to be linked to one or more chemicals, as appropriate. Respondents named 1347 different pesticides (or pesticide-targeted species) used on the farm, at non-farm jobs, or at home. Database usefulness was assessed by comparing numbers of responses naming actual chemicals to total responses linked to those chemicals. Sixty percent of farm pesticide, 59% of non-farm occupational, and 65% of house and garden responses named products, not chemicals. Among farm pesticide users, 182 (46%) reported using a total of 440 pesticides 1 to 40 years (mean 8.5 years) before those pesticides actually were marketed. The NIOSH-RPRD, now available to other investigators, has been a useful tool for us and other researchers to evaluate, group, and correct pesticide responses.

Single-nucleotide polymorphisms in selected cytokine genes and risk of adult glioma.

A role of immunological factors in glioma etiology is suggested by reports of an inverse relationship with history of allergy or autoimmune disease. To test whether single-nucleotide polymorphisms (SNPs) in cytokine genes were related to risk of adult glioma, we genotyped 11 SNPs in seven cytokine genes within a hospital-based study conducted by the National Cancer Institute and an independent, population-based study by the National Institute for Occupational Safety and Health (overall 756 cases and 1190 controls with blood samples). The IL4 (rs2243248, -1098T>G) and IL6 (rs1800795, -174G>C) polymorphisms were significantly associated with risk of glioma in the pooled analysis (P trend = 0.006 and 0.04, respectively), although these became attenuated after controlling for the false discovery rate (P trend = 0.07 and 0.22, respectively). Our results underscore the importance of pooled analyses in genetic association studies and suggest that SNPs in cytokine genes may influence susceptibility to glioma.

The Upper Midwest Health Study: a case-control study of primary intracranial gliomas in farm and rural residents.

Since several studies indicated that farmers and agricultural workers had an excess risk of brain cancer, the National Institute for Occupational Safety and Health initiated the Upper Midwest Health Study to examine risk of intracranial glioma in the non-metropolitan population. This population-based, case-control study evaluated associations between gliomas and rural and farm exposures among adults (ages 18 to 80) in four upper midwestern states (Iowa, Michigan, Minnesota, Wisconsin). At diagnosis/selection, participants lived in non-metropolitan counties where the largest population center had fewer than 250,000 residents. Cases were diagnosed 1 January 1995 through 31 January 1997. Over 90% of 873 eligible ascertained cases and over 70% of 1670 eligible controls consented to participate. Participants and nonparticipants, evaluated for "critical questions" on main and refusant questionnaires, differed significantly in farming and occupational experience, ethnicity, education, and lifestyle. The 1,175 controls were more likely than the 798 cases to have reported ever drinking alcohol (77% vs. 73%, adjusted odds ratio (OR) 0. 73, 95% confidence interval (CI) 0.59-0.92) and having had panoramic dental x-rays (34% vs. 29%, OR 0. 75, CI 0.61-0.92). Controls spent a greater percentage of their lives in non-metropolitan counties (78% vs. 75%, OR 0.81, CI 0.67-1.09). Among ever-farmers, controls were more likely to have had exposure to farm insecticides (57% vs. 50%, OR 0.75, CI 0.59-0.95) and farm animals (96% vs. 91%, OR 0.48, CI 0.25-0.90). Moving to a farm as an adolescent (ages 11 to 20) vs. as an adult was associated with a greater risk of glioma. In our study sample, farm or rural residence and summary farm exposures were associated with decreased glioma risk. However, nonparticipation by never-farming eligible controls could have affected results. Comparisons of farm chemical exposures may clarify associations between farming and glioma that others have reported.

Procedure for the quantification of the biomarker (2-methoxyethoxy)acetic acid in human urine samples.

An accurate and precise procedure was developed for the detection and quantification of (2-methoxyethoxy)acetic acid (MEAA), a metabolite and biomarker for human exposure to 2-(2-methoxyethoxy)ethanol. The compound 2-(2-methoxyethoxy)ethanol has a wide array of industrial applications including its use as an additive in military jet fuel. Exposure to 2-(2-methoxyethoxy)ethanol is a health concern owing to its toxicity which includes developmental and teratogenic properties. Sample preparation consisted of liquid-liquid extraction (LLE) and esterification of MEAA to produce the ethyl ester. Measurement was by a gas chromatograph (GC) equipped with a mass selective detector (MSD) using a HP-1 capillary column. Recovery studies of spiked blank urine demonstrated good accuracy and precision; recovery varied between 95 and 103% with relative standard deviations of 8.6% and less. The limit of detection (LOD) for this procedure was found to range from 0.02 to 0.08 microg/ml equivalent levels of MEAA in urine. These data and other aspects of the validation of this procedure will be discussed.

The relationship between sexual size dimorphism and habitat use in Greater Antillean Anolis lizards.

Sexual size dimorphism (SSD) is the evolutionary result of selection operating differently on the body sizes of males and females. Anolis lizard species of the Greater Antilles have been classified into ecomorph classes, largely on the basis of their structural habitat (perch height and diameter). We show that the major ecomorph classes differ in degree of SSD. At least two SSD classes are supported: high SSD (trunk-crown, trunk-ground) and low SSD (trunk, crown-giant, grass-bush, twig). Differences cannot be attributed to an allometric increase of SSD with body size or to a phylogenetic effect. A third explanation, that selective pressures on male and/or female body size vary among habitat types, is examined by evaluating expectations from the major relevant kinds of selective pressures. Although no one kind of selective pressure produces expectations consistent with all of the information, competition with respect to structural habitat and sexual selection pressures are more likely possibilities than competition with respect to prey size or optimal feeding pressures. The existence of habitat-specific sexual dimorphism suggests that adaptation of Anolis species to their environment is more complex than previously appreciated.

Serum organochlorine levels and breast cancer: a nested case-control study of Norwegian women.

This study investigated the potential association between organochlorine exposure and breast cancer using stored sera collected from 1973 through 1991 from the Janus Serum Bank in Norway. Breast cancer cases were ascertained prospectively from among 25,431 female serum bank donors. A total of 150 controls were matched to cases by birth dates and dates of sample collection. One g of serum per subject was analyzed for a total of 71 organochlorine compounds. For 6 pesticides [B-hexachlorocyclohexane, heptachlor epoxide, oxychlordane, trans-nonachlor, p, p'-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene, and p, p'-2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane] and 26 individual polychlorinated biphenyl (PCB) congeners there were >90% of samples over the limit of detection. There was no evidence for higher mean serum levels among cases for any of these compounds, nor any trend of increasing risk associated with higher quartiles of exposure. The remaining compounds (including dieldrin) were analyzed with respect to the proportion of cancer cases and controls having detectable levels; no positive associations were noted in these analyses. Our study did not confirm the recent findings of a Danish study of increased concentrations of dieldrin in the serum of breast cancer cases. The evidence to date on the association between serum organochlorines is not entirely consistent, but there is accumulating evidence that serum levels of p, p'-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene and total PCBs are not important predictors for breast cancer in the general population. Studies to date have not been able to evaluate whether exposure to highly estrogenic, short-lived PCB congeners increases breast cancer risk, nor have they fully evaluated the risk associated with organochlorine exposure in susceptible subgroups or at levels above general population exposure, including women with occupational exposure.

O(6)-methylguanine DNA adducts associated with occupational nitrosamine exposure.

Occupational nitrosamine exposures from a rubber vehicle seal (VS) curing operation were compared with the peripheral blood lymphocyte concentrations of two nitrosamine-related DNA adducts, N(7)-methylguanine (N(7)mdG) and O(6)-methylguanine (O(6)mdG), and with the activity of the enzyme that repairs O(6)mdG adducts, O(6)-alkylguanine-DNA alkyltransferase (AGT). The occupational personal breathing zone (PBZ) nitrosamine exposures ranged from 0.4 to 9.3 microg/m(3) in the VS area, from 0.1-2 microg/m(3) in an area remote from the VS and were not detected at a nearby rubber plant. Workers from all three of these locations had detectable concentrations of N(7)mdG adducts, ranging from 0.1 to 133.2 adducts/10(7) deoxyguanosine nucleosides. Although N(7)mdG concentrations were elevated for those who worked in the VS area (median 3.60 compared with 1.44), the difference was not statistically significant after controlling for confounding factors. The O(6)mdG adduct concentrations were much lower than those of N(7)mdG, ranging from non-detectable to 12.7 O(6)mdG adducts/10(7) deoxyguanosine nucleosides and many of the participants (40/78 successfully analyzed) did not have detectable amounts of these adducts (limit of detection 0.03 O(6)mdG adducts/10(7) deoxyguanosine nucleosides). Analysis of the ordinal exposure categories (high, medium/high, medium/low, low and no exposure) yielded a statistically significant association with having detectable O(6)mdG adducts (Kendall's taub = -0.253, asymptotic SE = 0.096). There was no significant association between AGT activity and nitrosamine exposure or exposure category (P > 0.30). Although no association was found between PBZ exposure and either the N(7)mdG adduct concentrations or AGT activity, the significant positive association between working in and near the VS department and the presence of O(6)mdG adducts, which have mutagenic potential, provides evidence to link nitrosamine exposure one step closer to human cancer by demonstrating an association between external nitrosamine exposures and cancer-related biological effects.

Intensive care unit bedside documentation systems. Realizing cost savings and quality improvements.

Automating intensive care unit (ICU) documentation saves time and assists in interpreting data and planning care. The current economic climate makes the cost of ICU computer systems prohibitive for many institutions. Any expenditure without a measurable return on investment will be scrutinized carefully. The literature describing ICU computer system benefits often is difficult to interpret. No two implementations, hospitals, or benefit study designs have been the same. Each implementation has many unique variables. These variables make study comparison and replication potentially impossible. The authors have concluded that replicating previous studies may not be relevant if the goal is to justify system cost. The objective is met by designing a study that evaluates changes in data management activities as well as issues unique to the study unit or institution. The purpose of this article is to review the findings of previous benefits studies related to ICU documentation systems and to suggest other measures to support cost justification for expensive bedside documentation systems.

Laser surface profiler.

By accurate measurement of the angle of reflection of a laser beam that is incident upon a reflective surface with a position-sensitive detector, changes in the surface-normal direction (the slope or the derivative of the surface) can be determined directly. An instrument has been built that makes repeated measurements over the surface and uses the collected data to produce a gray-scale image of the slope. The resolution of this system for detecting changes in the surface-normal direction is found to be better than 0.01 degrees . By focusing of the laser beam to achieve a lateral resolution of 5 mum , the resolvable surface-height change owing to a variation in slope is estimated to be <1 nm .

Occupational applications of a human cancer research model.

Many bladder cancers are indolent, and since there are no biomarkers to predict progression, the prognosis is problematic. Utilizing an in vitro/in vivo human uroepithelial cell (SV-HUC.PC) transformation system, we investigated several molecular events occurring along the continuum of exposure to disease outcome as potential biomarkers for occupational carcinogenesis. The model also served to generate information on the occupational carcinogenicity of N-hydroxy-4,4'-methylene bis(2-chloroaniline) [N-OH-MOCA]. Two of 14 groups of SV-HUC.PC treated with various concentrations of N-OH-MOCA formed carcinomas in athymic nude mice. Each of the biomarkers investigated demonstrated potential for interventions/prevention applications of occupational bladder cancers but will require validation and further evaluation. Those investigated displaying potential occupational utility included the induction of ornithine decarboxylase (ODC), DNA adducts, and altered proteins, as detected on HUC two-dimensional polyacrylamide gel electrophoresis protein maps.

The Mars oxidant experiment (MOx) for Mars '96.

The MOx instrument was developed to characterize the reactive nature of the martian soil. The objectives of MOx were: (1) to measure the rate of degradation of organics in the martian environment; (2) to determine if the reactions seen by the Viking biology experiments were caused by a soil oxidant and measure the reactivity of the soil and atmosphere: (3) to monitor the degradation, when exposed to the martian environment, of materials of potential use in future missions; and, finally, (4) to develop technologies and approaches that can be part of future soil analysis instrumentation. The basic approach taken in the MOx instrument was to place a variety of materials composed as thin films in contact with the soil and monitor the physical and chemical changes that result. The optical reflectance of the thin films was the primary sensing-mode. Thin films of organic materials, metals, and semiconductors were prepared. Laboratory simulations demonstrated the response of thin films to active oxidants.

Synthetic infrared spectra.

We have designed, microfabricated, and characterized a diffractive optical element that reproduces the infrared spectrum of HF from 3600 to 4300 cm(-1) . The reflection-mode diffractive optic consists of 4096 lines, each 4.5mum wide, at 16 discrete depths relative to the substrate from 0 to 1.2 mum and was fabricated upon a silicon wafer by anisotropic reactive ion-beam etching in a four-mask-level process. We envisage the use of diffractive optical elements of this type as the basis for a new class of miniaturized, remote chemical sensor systems based on correlation spectroscopy.

Synthetic spectra: a tool for correlation spectroscopy.

We show that computer-generated diffractive optical elements can be used to synthesize the infrared spectra of important compounds, and we describe a modified phase-retrieval algorithm useful for the design of elements of this type. In particular, we present the results of calculations of diffractive elements that are capable of synthesizing portions of the infrared spectra of gaseous hydrogen fluoride (HF) and trichloroethylene (TCE). Further, we propose a new type of correlation spectrometer that uses these diffractive elements rather than reference cells for the production of reference spectra. Storage of a large number of diffractive elements, each producing a synthetic spectrum corresponding to a different target compound, in compact-disk-like format will allow a spectrometer of this type to rapidly determine the composition of unknown samples. Other advantages of the proposed correlation spectrometer are also discussed.

Fewer immigrants settle in nonmetro areas and most fare less well than metro immigrants.

"Recent attention to the issue of immigration in the United States has led to the addition of questions about immigration status to the Current Population Survey. Data from the March 1996 version show that Mexico has been the single largest source of immigration to the nonmetro United States, that a large proportion of nonmetro immigrants are children, and that nonmetro immigrants generally have lower earnings, higher unemployment, and higher poverty rates than metro immigrants and nonmetro natives. Fewer immigrants live in nonmetro areas than in metro, but they are concentrated in particular areas."

College students' attitudes toward finding a mate to escape depression: sex differences.

College student respondents (n = 128) were compared on their consideration of finding a mate or significant other as a strategy for a hypothetical teacher ("Terry") displaying symptoms of dysthymic disorder (DSM-IV criteria). The sex of "Terry" was manipulated by descriptive pronoun (he or she) only. Analysis indicated differences based on sex of Terry and sex of respondent. Respondents favored finding a mate for the hypothetical male more than the female. Men, more than women, supported finding a mate or significant other for the teacher.

The impact of interindividual variation in NAT2 activity on benzidine urinary metabolites and urothelial DNA adducts in exposed workers.

Several epidemiologic studies indicate that NAT2-related slow N-acetylation increases bladder cancer risk among workers exposed to aromatic amines, presumably because N-acetylation is important for the detoxification of these compounds. Previously, we showed that NAT2 polymorphisms did not influence bladder cancer risk among Chinese workers exposed exclusively to benzidine (BZ), suggesting that NAT2 N-acetylation is not a critical detoxifying pathway for this aromatic amine. To evaluate the biologic plausibility of this finding, we carried out a cross-sectional study of 33 workers exposed to BZ and 15 unexposed controls in Ahmedabad, India, to evaluate the presence of BZ-related DNA adducts in exfoliated urothelial cells, the excretion pattern of BZ metabolites, and the impact of NAT2 activity on these outcomes. Four DNA adducts were significantly elevated in exposed workers compared to controls; of these, the predominant adduct cochromatographed with a synthetic N-(3'- phosphodeoxyguanosin-8-yl)-N'-acetylbenzidine standard and was the only adduct that was significantly associated with total BZ urinary metabolites (r = 0.68, P < 0.0001). To our knowledge this is the first report to show that BZ forms DNA adducts in exfoliated urothelial cells of exposed humans and that the predominant adduct formed is N-acetylated, supporting the concept that monofunctional acetylation is an activation, rather than a detoxification, step for BZ. However, because almost all BZ-related metabolites measured in the urine of exposed workers were acetylated among slow, as well as rapid, acetylators (mean +/- SD 95 +/- 1.9% vs. 97 +/- 1.6%, respectively) and NAT2 activity did not affect the levels of any DNA adduct measured, it is unlikely that interindividual variation in NAT2 function is relevant for BZ-associated bladder carcinogenesis.

Neoplastic transformation and DNA-binding of 4,4'-methylenebis(2-chloroaniline) in SV40-immortalized human uroepithelial cell lines.

The tumorigenic transformation of certain occupationally significant chemicals, such as N-hydroxy-4-4'-methylenebis[2-chloroaniline] (N-OH-MOCA), N-hydroxy-ortho-toluidine (N-OH-OT), 2-phenyl-1,4-benzoquinone (PBQ) and N-hydroxy-4-aminobiphenyl (N-OH-ABP) were tested in vitro using the well established SV40-immortalized human uroepithelial cell line SV-HUC.PC. SV-HUC cells were exposed in vitro to varying concentrations of N-OH-MOCA, N-OH-OT, N-OH-ABP and PBQ that caused approximately 25% and 75% cytotoxicity. The carcinogen treated cells were propagated in culture for about six weeks and subsequently injected subcutaneously into athymic nude mice. Two of the fourteen different groups of SV-HUC.PC treated with different concentrations of N-OH-MOCA, and one of the three groups exposed to N-OH-ABP, formed carcinomas in athymic nude mice. 32P-postlabeling analyses of DNA isolated from SV-HUC.PC after exposure to N-OH-MOCA revealed one major and one minor adduct. The major adduct has been identified as the N-(deoxyadenosin-3',5'-bisphospho-8-yl)-4-amino-3-chlorob enz yl alcohol (pdAp-ACBA) and the minor adduct as N-(deoxyadenosin-3',5'-bisphospho-8-yl)-4-amino-3-chlorot oluene (pdApACT). Furthermore, SV-HUC.PC cytosols catalyzed the binding of N-OH-MOCA to DNA, in the presence of acetyl-CoA, to yield similar adducts. The same adducts were also formed by chemical interaction of N-OH-MOCA with calf thymus DNA, suggesting that the aryl nitrenium ion may be the ultimate reactive species responsible for DNA binding. The tumorigenic activity of N-OH-MOCA in this highly relevant in vitro transformation model, coupled with the findings that SV-HUC.PC cells formed DNA-adducts in vitro and contained enzyme systems that activated N-OH-MOCA to reactive electrophilic species that bound to DNA, strongly suggest that MOCA could be a human bladder carcinogen. These findings are consistent with the International Agency for Research on Cancer's classification of MOCA as a probable human carcinogen.

Normal glomerular organization of the antennal lobes is not necessary for odor-modulated flight in female moths.

A prominent hypothesis for the function of the glomerular structures in the primary olfactory neuropil of many groups of vertebrate and invertebrate animals is that they enable the processing and coding of information about the chemical compounds that compose complex odors. Previous studies have indicated that various degrees of glomerulus formation in the antennal lobes of the brain of the moth Manduca sexta can be effected by reducing the number of olfactory sensory axons that grow from the antenna into the antennal lobe during metamorphosis. To test the hypothesis that the presence of glomerular structure is necessary to process and identify odors, we substantially reduced, by surgery, the number of antennal segments in developing moths and upon metamorphosis we observed and quantified behavioral responses known to be elicited by odors. Intact and lesioned adult female moths were challenged to fly upwind to the source of an attractive host-plant odor in a wind tunnel. Some of the moths that had developed with reduced olfactory input flew upwind to the odor source. The flight behavior of these individuals was similar to the odor-mediated flight typically observed in moths that had developed normally. Histological analysis of the moths' antennal lobes revealed that the lobes of more than half of the respondents that had been lesioned during development lacked normal glomerular organization. The neuropil of these abnormally developed antennal lobes was mostly aglomerular, but with a few isolated, clearly abnormal glomerulus-like structures. This suggests either that even a few abnormal glomeruli are sufficient to mediate this specific behavior or that "canonical" glomerular organization per se is not necessary for this odor-mediated behavior.

Metabolic activation and DNA adduct detection of PhIP in dogs, rats, and humans in relation to urinary bladder and colon carcinogenesis.

The metabolic activation of the heterocyclic amine carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was examined in dogs and rats as models for urinary bladder and colon carcinogenesis, respectively. The results indicate that unconjugated N-OH-PhIP is not excreted in the urine after oral dosing with PhIP and that the two isomeric N-glucuronides of N-OH-PhIP, which are formed as major metabolites, are stable under acidic conditions. These data suggest that PhIP is unlikely to serve as a urinary bladder carcinogen in either species. Using metabolic inhibitors, bile duct ligation, and intravenous dosing studies, a new hypothesis for colorectal carcinogenesis is proposed involving N-oxidation of PhIP by hepatic cytochrome P-4501A2 (CYP1A2) and O-acetylation by the polymorphic acetyltransferase (NAT2). The resulting N-hydroxy and N-acetoxy metabolites both appear to be transported through the circulation to the colon mucosa, forming covalent DNA adducts. Glucuronidation and reaction with glutathione appear to serve as detoxification pathways. In humans, individuals who are phenotypically rapid metabolizers for both CYP1A2 and NAT2 are significantly higher (p = 0.0015) in colorectal cancer/poly cases vs. controls; and PhIP-DNA adducts can be detected in human colon samples. These studies provide strong evidence that PhIP and other heterocyclic amines play an important role in the etiology of human colorectal cancer.