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Try out PMC Labs and tell us what you think. Learn More. Due to OSHPD restrictions for the confidential version of hospital data, our protocol does not permit data sharing. All SAS programs are available on request. Additional files 1, 234 and 5 are described below. We use longitudinal hospital data to compare reproductive outcomes for two generations in Willits and two generations in the Rest of County ROC. This is the first study to quantify the reproductive impact of Cr VI in a non-occupational population.

We searched California hospital discharge data — to find Mendocino County residents born or later. First, we calculated the crude birth rate using an external census denominator. The next two models used self-contained denominators to assess health of infants and two generations of pregnant women. Finally, we focused on non-pregnant females and, for comparison, males. Here we added admissions for people who moved, linked and summarized admissions to the person level, and calculated rates per census population. We found newborn records in ROC and from Willits. At start of period, Willits birth rate was low and did not recover until 12 years after Plant closure.

While the Plant was open, respiratory conditions, perinatal jaundice, and birth defect rates were higher for Willits infants compared to ROC, but improved post-closure. During the period under study, we identified admissions of pregnant ROC women and from Willits. Willits women had ificantly higher risk of pregnancy loss compared to ROC, whether stratified by generation, age group, or pre- and post-closure.

Regardless of when exposed, Willits women continued to have ificantly higher rates of in-hospital terminations, as animal studies of Cr VI exposure predict. In life course models, non-pregnant Willits women have ificantly higher risk of reproductive organ conditions and neoplasms compared to ROC. Adverse reproductive outcomes are elevated and consistent with animal studies.

General health outcomes reflect the same broad effect reported for occupationally exposed workers. For the first time, the detrimental reproductive effects of non-occupational Cr VI exposure in human females and their infants is reported. The online version of this article doi Ina small auto shop expanded to a machine shop the Plant [ 1 ]. Bythe Plant manufactured heavy-duty steel cylinders [ 2 ] and, by the early s, militarily-classified intercontinental ballistic missile cylinders [ 34 ].

Steel was hardened with hexavalent chromium mist Cr VI which floated through vents in the Plant, polluting the air in Willits. At the top of the Eel River watershed, the Plant dumped toxic waste into local creeks and contaminated ground water at four sites in and near Willits [ 5 ]. After years of turmoil and investigations [ 6 — 11 ], the Plant declared bankruptcy, closing in late [ 12 ].

Years later, Agency for Toxic Substances and Disease Registry ATSDR investigators began to report increased risk of adverse health outcomes among Willits residents exposed to Cr VI emissions and ordered remediation to protect public health [ 13 — 18 ]. Remediation continues twenty years after closure [ 5 ]. In reports for ATSDR, Underwood and colleagues [ 1417 ] highlighted that few health studies address non-occupational exposure to environmental toxins, and that little is known about the long-term effect for men and women exposed during childhood or the reproductive period.

Consistent with the Environmental Protection Agency EPA [ 19 ], they recognized that infants and children may be more sensitive to environmental exposures than adults, characterized risks to children in the Willits area, and felt information was needed on people who were children at the time of exposure. As a last point, they noted that research on the effect of Cr VI on children was an area with virtually no scientific information [ 17 ]. However, as exposure began so many years earlier, Harrison thought that too much time had elapsed to study outcomes [ 20 ]. These reports motivated Remy and Clay to use longitudinal hospital data to begin to assess health status for Willits [ 21 ].

After evaluating to census data, they concluded that Willits and the rest of the County ROC were among the more residentially stable areas in California and were demographically similar. Using hospital discharge abstracts over the periodcensus-based population denominators, and a cross-sequential life course de [ 22 ], they found that Willits residents had a ificant increase in illness compared with ROC. This paper continues the investigation, now focused on women born between andreproductive age 15 to 44 when first hospitalized for any reason between andand infants born over the same period.

Primary data is hospital discharge abstracts, examining outcomes for infants, pregnant and non-pregnant women and, for comparison, men. Availability of this data allowed us to investigate the reproductive health of two generations of mothers and infants born to them. The generational focus allowed us to examine reproductive consequences for mothers exposed to Cr VI at different life stages and their babies.

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However, most of the older generation born — were not exposed until puberty and conceived when the Plant was open —while most of the younger generation born — were exposed in utero, during childhood, and conceived after closure — Although the Plant exposed Willits to various chemicals, we focus on Cr VI as the exposure of most concern for adverse outcomes.

Cr VI attracted the primary interest of regulatory agencies that concluded past exposures affected community health [ 14 ]. This toxic makes its way into the domestic environment when facilities emit contaminated air, which then enters nearby water and soil. Principal non-occupational exposures occur by breathing contaminated air or drinking contaminated water. A large body of research established serious reproductive toxicity in female and male animals and occupationally exposed men [ 23 ]. A major report summarized five studies of female animals exposed to Cr VI during gestation, and four of female animals exposed before reproductive age, with a focus on the resultant litters [ 24 ].

The first five studies had similar findings: increased pre- and post-implantation loss, resorption frequency, more dead and fewer fetuses per litter, low fetal weight, renal pelvis dilation, and bone or skeletal defects. In the second group of studies, exposure occurred long before mating.

on litters were strikingly similar to litters of females exposed during gestation: decreased implantation, decrease in live fetuses, increased resorption frequency, and bone or skeletal defects. Others added more information on defects [ 2526 ] and reproductive organ damage [ 27 — 29 ]. Authors of one report [ 30 ] in the review felt that decreased s of implantation sites and viable fetuses, and increased resorption suggested disturbance of reproductive endocrine functions with multiple sites of toxicity along the hypothalamic-pituitary-ovarian uterine axis. They also suggested increased resorption was due to modification of the uterine lining before arrival of the embryo.

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The of corpora lutea also decreased [ 31 — 34 ]. Premature ovarian failure POF was noted when litters of exposed mothers reached reproductive age. Exposure during prenatal development causes POF in progeny by altering the expression pattern of certain enzymes in fetal ovaries [ 3335 ]. Whether exposed before or during gestation, most studies found an increase in chromium levels in the placenta, suggesting Cr VI accumulates in maternal tissues during treatment, remains during the untreated mating period, and crosses the placenta into fetuses during gestation [ 24 ].

In exposed male experimental animals and male humans, sperm viability, motility, and morphology is abnormal, and male workers report frequent spontaneous abortions in spouses [ 2436 ].

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Only five studies describe adverse reproductive effects in occupationally exposed women. Similar to animal studies, these found: increased spontaneous abortions [ 37 ]; decreased intrauterine growth of fetuses resulting in low birth weight [ 3839 ]; high levels of Cr VI in the blood, urine, and umbilical cord blood [ 3840 ]; and in neonates, Cr VI in the cord blood and cord lymphocyte mutations [ 3241 ].

Here, we examine if similar outcomes occurred in a domestically exposed population of infants and pregnant women over the year period —, comparing women exposed during and after their reproductive years with those exposed only as children. We also examine the available life course data for non-pregnant women age 15 to 44 at some point in the year period Jul through Dec, when the oldest was about 64 years old. For comparison, we did a life course analysis for males. The term "County" describes the large, rural, sparsely populated area of Mendocino County.

The comparison is to residents in the rest of the County ROC unexposed. The ZIP-code area enclosing Willits proper includes dispersed housing located in redwood wilderness, agricultural lands, and Native American rancherias. California releases county-level population estimates by age and sex annually, but sub-county population is available only every 10 years from the census. From the,and censuses, we obtained county and ZIP-code population by age and sex [ 43 — 47 ]. Within age and sex, we calculated the percent of Mendocino County population in Willits.

We interpolated these percentages to obtain estimated percents for intercensal years, and extrapolated through using the — rates of change. For each age, sex, and year we multiplied the Willits percent times the county population estimate yielding a Willits estimate. We subtracted this from the county population to get ROC population. Finally, we approximated birth year by subtracting the age of the population estimated from the year of the estimate. For example, the population age 44 in was born in Summing annual populations within geography, sex and birth cohort yielded total person-years, used as the denominator to calculate crude birth rates and rates for life course models.

These files were prepared ly for longitudinal research with methods described elsewhere [ 48 ]. The CCS clusters diagnoses and procedures into a manageable of clinically meaningful. Following methods used by the Healthcare Cost and Utilization Project [ 51 ], conditions were identified by searching all available fields.

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See Additional file 1 for descriptions of groupers to select records and classify conditions. From first year data are available through last year available when we began this studywe extracted discharges with birth year forward, admitted while living in the County. For life course models non-pregnant females and maleswe added admissions after people moved from the County. Population denominators were the total populations of these areas by year.

We estimated crude birth rates CBR as the of births per population. The CBR analysis used Point to fit piecewise linear models and to test for ificant changes in slope between ading pieces [ 5253 ]. We examined reproductive outcomes using hospital discharges of infants and pregnant women. Because newborn infants rarely have SSNC and mothers had them only sincethese were unlinked records of County residents from —, identified at discharge as living in Willits or ROC. The infant file included newborn discharge records plus post-newborn records with age at admission less than one year.

Post-newborn records are essential in picking up transfers and conditions often not noticed at birth. To check certain assumptions, a secondary analysis linked records for babies who were the only birth in the County on a given day. The pregnant women analysis file included any discharge record with a pregnancy diagnosis, age at discharge from 15 to 44 years, and year of birth in the interval to Models for infants and pregnant women examined the rate of occurrence for various outcomes as a percent of discharge records, within Willits and ROC, with relative risk models comparing exposed Willits to unexposed ROC rates.

In relative risk models, the rate numerator was the of discharges with the outcome and the denominator was the of newborn or delivery discharges, with rates rescaled per For infants, we stratified by birth period as before — or after — Plant closure. We ended the pre-closure period in because the Plant closed in Dec [ 12 ] and parents conceived most births in For pregnant females, we stratified by year generation born —, —age at pregnancy 15—24, 25—34, 35—44and whether the pregnancy was before or after Plant closure.

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were so similar we focused on generation. Thus, the reported models focus on when people were born. In life course cross-sequential models [ 22 ] for non-pregnant women and men, we define a person as the combination of SSNC, sex, and birth year. We include sex to identify a person because never-employed spouses can use their partner's SSNC [ 49 ]. Thus, we had a high likelihood of identifying adults no longer living in the County if admitted at least once while living there.

In making these files, we excluded records lacking SSNC and SSNC with the same sex and more than one birth year or too many races or discharges, suggesting poor linkage.

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We made life course files for non-pregnant females and males reported tangentially to assess general health, health of reproductive organs, and cancers. These models used discharges from age 15 through maximum age in about 64including discharges after people moved out-of-county. We first searched the recorded diagnoses and procedures on each record to flag conditions of interest. Summarizing records within person, a condition was set to 1 true if found on any record. We summarized person-level data by generation, divided summarized condition counts by external population estimates, and rescaled the resulting rate per 10, person years.

One County hospital did not use SSNC as part of its medical record system and we were unable to link records. Of women with more than one record, lived in both areas.

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When reportingwe restrict use of the word ificant to reflect statistical ificance, specifically when the 2-tailed P -value is less than or equal to 0. Without stratification, chi-square tests assessed the statistical ificance of relative risk RR with regard to exposure, with RR greater than 1 indicating greater risk in Willits.

These models assessed data within a given interval e.

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Table 1 shows, by year generation and year cohort within generation, potential exposure periods for people who ever lived in Willits. The table also shows of records extracted for the four core models we developed: infant, pregnancy, non-pregnant female life course, and male life course.

of records extracted by generation, exposure, model, and Plant period, Table 1 addresses two important points. Second, focusing on Pregnancy rows, only admissions occurred post-closure among women born between andwhile all but 43 admissions occurred post-closure among women born between and This is the only birth interval containing both infants and parents. Fertility is a standard measure of population health, specifically the CBR per population. The Plant began using Cr VI 20 years earlier, before data were available. California trends changed in andwhile ROC trends changed in and By contrast, Willits CBR declined steadily through before beginning to increase.

Inflection or points have larger round circles. We next turned attention to infant outcomes. Between andwe found discharges of ROC infants and of Willits infants age less than one year. ROC had newborn records and Willits had Table 2 shows three groups of infant outcomes: conditions originating in the perinatal period, other general body system conditions, and congenital anomalies.

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