Identify sources of environmental contaminants and pathways of exposure.

Describe the role environmental contaminants may play in reproductive health.

Support effective strategies for reducing harmful exposures to environmental contaminants.

Recognize the impact of direct-to-consumer advertising on clinical practice.

Discuss guidelines set forth by professional organizations to assist physicians in managing exposure to pharmaceutical marketing.

Environmental Contaminants and Reproductive Outcomes
Linda C. Giudice, MD, PhD, MSc, Robert B. Jaffee, MD, Endowed Professor and Chair, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, School of Medicine

Chemical production: explosive production of chemicals in United States since World War II; ≈75000 chemicals registered to commerce; ≈2800 high-production chemicals (>1 million pounds annually; complete toxicity data on only 7%); primary testing end points death of animal or development of fetal malformations; little data on reproductive outcome; no toxicity data for 43% of chemicals; source of data comes from humans, laboratory animals, and wildlife; ≈900 active ingredients in pesticides; ≈3000 chemicals in food; ≈5000 chemicals in pharmaceuticals and cosmetics; average American woman uses 12 personal-care products daily; average American teenage girl uses 17; evaluating evidence base— pharmaceuticals must show efficacy and safety to Food and Drug Administration (FDA); chemicals need to show harm before being removed; generally, harm has to affect population or individuals; manufacturers not responsible for determining or compensating for harm; responsibility falls on regulatory agencies (often underfunded) or advocacy groups; exposure to environmental contaminants mostly unintended side effect; concern about reducing harmful exposures requires different level of proof; need to be concerned about false positives and false negatives

Sources and pathways of exposure: ozone, particulate matter, lead, and hazardous pollutants from industrial waste; air pollution from motor vehicles; agricultural and household pesticides end up in water supply; items put in mouth by young children significant pathway of exposure; phthalates in personal-care products; bisphenol A (BPA) present in baby bottles and plastic lining of cans; household dust and furniture (reservoirs of chemicals)

Chemical features: persistent and bioaccumulative types—persist in environment and in people; magnify higher up on food chain; eg, dichlorodiphenyltrichloroethane (DDT), polychlorinated biphenyl (PCB), dioxins, mercury; nonpersistent compounds—many chemicals have relatively short half-lives in humans; eg, phthalates, BPA, perchlorate, solvents; transient exposure may be harmful for fetus; Centers for Disease Control and Prevention (CDC) collects nationally representative data on body burdens of environmental contaminants; evidence of environmental tobacco smoke (ETS), lead, mercury, phthalates, BPA, perfluorinated compounds, and perchlorate in almost everyone; compounds alone may not have estrogenic effects but, combined with estrogens, may augment estrogen action; most testing done one chemical at a time

What science tells us: multiple chemical exposures can have magnified effects; exposures can have short-term and long- term consequences; pregnancy, infancy, childhood, and adolescence vulnerable times for exposure; pregnancy trends, chemicals, and reproductive outcomes—limited data; shift in distribution of term “gestation” (on average, 40 wk in 1992 and 39 wk in 2002); median birth weight at 40 wk for singleton births has been declining over 20-yr period

Air pollution: ETS known risk factor for low birth weight (LBW) and preterm birth; in animal study (Rocha), mice kept in chamber with dirty air (vs mice kept in chamber with clean air) had offspring with LBW, and lower placenta weight also seen; speaker wonders what data might show about pregnant women living close to freeways; role of air pollution on LBW and preterm birth effects likely small, but exposure ubiquitous; ≈30-g reduction in birth weight for every 10 µg/m3 increase in particulate air pollution in state of California (20-30-g reduction for ETS); critical windows variable

Drinking water: disinfection byproducts—moderate evidence of contribution to LBW; pesticides—limited studies; intrauterine growth restriction (IUGR) increased in southern Iowa communities with highest levels of pesticides (Munger)

Congenital anomalies and occupational exposures: solvents—retrospective meta-analysis showed 1.64 odds ratio (OR) for major malformations; prospective study showed 13.0 OR for major malformation; glycol ethers—OR high for congenital malformation, including neural tube defects, multiple anomalies, and cleft lip; suggestion of increased risk for miscarriage; reinforces the importance of taking thorough prenatal history (eg, occupation and place of residence) in patient having multiple unexplained miscarriages

Fertility: trend shows increase in impaired fecundity over 20-yr period (8% in 1992 vs 12% in 2002); doubling of involuntary infertility among women 15 to 24 yr of age in last 20 yr; sperm counts and testosterone levels dropping in industrial countries (not in developing countries)

Hypospadias: rate increasing over 22-yr period (not due to increase in diagnosis); increase in testicular germ cell tumors; believed attributable to disruption of development of fetal testes; testicular dysgenesis syndrome—begins with impaired spermatogenesis (mild form); impaired spermatogenesis with undescended testes (medium form); impaired spermatogenesis, undescended testes and hypospadias (severe form; associated with increased risk for testicular cancer); endocrine disruptors or other disruption during fetal testicular development may play role

Endocrine-disrupting chemicals (EDCs): exogenous agents that interfere with synthesis, secretion, transport, metabolism, binding action, or elimination of hormones; responsible for metabolic homeostasis, reproduction, and developmental process; affect reproductive potential, including timing of puberty, menstruation (volume, timing, frequency), endometriosis, time to pregnancy, pregnancy loss, reproductive senescence, sperm counts, and pregnancy outcomes; studies in women—evidence of increased fetal loss, stillbirth, and birth defect syndrome close to agricultural areas sprayed with pesticides; early breast development linked to EDCs (incidence of early breast development in children adopted from Eastern Europe); data show that female fetuses exposed to DDT in utero have longer time to pregnancy when adults; exposure to diethylstilbestrol (DES) transgenerational; phthalates linked to precocious puberty in girls; BPA—data from studies in mice show higher incidence of aneuploidy of ovaries and testes in fetuses of pregnant dams exposed to BPA; measurable; highest levels found in placental tissue; no demonstrated cause and effect (speaker proposes that findings deserve further investigation); dioxins—shown to cause premature reproductive aging in rats in dose-dependent manner; in adult nonhuman primates, exposure causes endometriosis; highest rate of severe endometriosis in Belgium (dioxin levels highest in world); in vivo animal data suggest dioxin may promote or augment endometriosis

Environmental tobacco smoke: reduced fecundity; decreased ovarian reserve; decreased success in in vitro fertilization (IVF); earlier menopause (by 1-4 yr; probably mediated by apoptosis of oocytes); increased spontaneous abortion rate; decreased fertility in daughters of smokers

Environmental exposures in men: environmental levels of phthalates in men with infertility associated with increased rates of sperm DNA damage, low sperm counts, and other abnormalities; BPA level correlates with decreased sperm counts; lower sperm counts correlate inversely with levels of pesticides in blood; data show decreased anogenital distance and penile length in male infants and boys who have higher levels of phthalates; decreased anogenital distance can result in more feminization of external genitalia

Canada’s chemical valley: community exposed to 23 million pounds of chemicals annually; associated with reproductive and developmental problems, as well as cancer; 40% risk for miscarriage in women <40 yr of age; 1:1 ratio of boys to girls born in 1999; currently, ratio 2:1 for girls to boys; EDCs and sex ratios—dependent on EDC exposure (holds true for paternal as well as maternal exposure); altered birth ratios seen in veterans returning from Iraq; no boys being born in some communities in Arctic circle

Working toward a solution

Studies: impact of reproductive toxicity may not be known until large-scale body burden studies conducted; National Health and Nutrition Examination Survey (NHANES)—biomonitoring data on typical exposures to chemicals, pesticides, cosmetics, and plastics; looking at preterm delivery or LBW (not reproductive outcomes); CDC—survey measuring 145 chemicals in 2500 people across United States; National Children’s Study—study (>100000 pregnant women, >20-yr period, and >105 communities in United States) tracking health of babies through adulthood; health tracking data should be mined for reproductive effects (eg, infertility, time to pregnancy, pregnancy loss, preterm delivery, congenital anomalies, IUGR, neonatal morbidity and mortality)

Policies and initiatives: some doubt science translatable to humans; others believe that gaps in knowledge should not prevent policy actions (ie, existing evidence sufficient to justify action); Cosmetic Directive in Europe requiring removal of phthalates from personal-care products and make-up; Registration, Evaluation and Authorisation of Chemicals (REACH) initiative in Europe requires chemical companies to demonstrate safety (so burden not on government); working toward solution requires leadership, social action, civic participation, and environmental education; physicians and other health care providers in position to raise awareness about environmental exposure and harm; University of California, San Francisco, in conjunction with American Association for Reproductive Health Professionals and American College of Obstetricians and Gynecologists (ACOG), has produced reproductive health tool kits reviewing science linking exposure to environmental contaminants to health

Pharmaceutical Marketing and Women’s Health
Carolyn Sufrin, MD, MA, Clinical Fellow in Family Planning, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, School of Medicine

Pharmaceutical industry: among top 5 most profitable industries in United States; research and development (R&D)— industry commonly claims $802 million needed to research and market single drug; does not include 34% tax deduction for R&D; significant percentage of research involved in developing drugs actually funded by National Institutes of Health (NIH); Boston consulting firm asserts cost of marketing new drug actually ≈$250 million ; review of 11 yr of approved patents and new drugs showed only 24% of 1035 new drugs represented significant improvements; “me too” drugs— slightly different molecular structure (eg, extended-release formulation) from drug already on market; manufacturer utilizes old approval for new indication; eg, Prozac (fluoxetine) redesigned as Sarafem (also fluoxetine) and remarketed for premenstrual dysphoric disorder

Direct-to-consumer (DTC) advertising: eg, print advertising, billboards, sponsorship at sporting events; prompts consumer to think about medications and ask physician; benefits—encourages people to seek medical care; encourages compliance with medications; marketing leads to competition, potentially lowering cost of drugs (however, direct control by consumers limited because physician acts as gatekeeper); risks—overtreatment with expensive drugs; confusing messages; biased information; de-emphasis of lifestyle modifications; potentially detrimental effects on physician-patient relationship; increased costs to consumers; safety concerns; perceptions/findings among consumers and health care professionals— DTC advertising noncomprehensive and contains inappropriate information; led only 4% to 10% of patients to seek care; physicians felt pressured to prescribe inappropriate medications; data show patient exposure to DTC advertising leads to requests for particular brands, and prescriptions often inappropriate

Pharmaceutical “detailing”: one-half sales pitch, one-half education; pharmaceutical representative provides “details” (ie, information) on product; efficient and purposeful way to market; >90000 pharmaceutical representatives in United Sates; ≈1 representative for every 6 to 9 physicians; ≈$8000 to $13000 spent per physician per year; benefits—education about new drugs in short time; convenient for physician; provides free samples for patients and useful items for physician; drawbacks—biased education (by design); influences prescribing; conflict of interest (COI); patient perception; cost of drugs; gifts—create implicit rules of reciprocity (whether consciously or unconsciously); reminder items create sense of brand loyalty; meals—sharing meal creates sense of shared experience; studies show patients question ethics of gift-giving; most physicians think meals, inexpensive gifts, and textbooks appropriate; number of studies show exposure to pharmaceutical representatives influences practice (eg, formulary addition request); benefits of samples—way to provide medications (albeit usually expensive heavily advertised ones) to those who cannot afford them; provides patient access to cutting-edge (but expensive) drugs; allows physician to get patient immediately started on medication; increases patient’s approval of physician; drawbacks of samples—usually blockbuster medications and not evidence-based medications; study showed use of first-line antihypertensive medications increased from 38% to 61% after samples prohibited in institution for 1 yr; study showed that, of 32000 patients receiving samples, only 28% below federal poverty level and fewer than one-fifth uninsured

Continuing medical education (CME) sponsorship: in 2006, pharmaceutical industry contributed $1.2 billion toward CME events; physicians do not believe they are influenced, but research (Orlowski JP) shows attending industry-sponsored CME affects practices in favor of industry; example—ACOG and United States Preventive Services Task Force recommend against universal herpes simplex virus (HSV) serology screening for pregnant women; however, universal screening being promoted by prominent perinatologists across country conducting industry-supported grand rounds

Position of professional organizations: American Medical Association (AMA)—gifts should entail benefit to patients and should be of minimal value; individual gifts of minimal value permissible as long as gift related to education; meals and conferences permissible as long as related to education and held at location appropriate for education; companies should not pay for physicians to attend conferences but can provide funds for trainees to attend conferences; ACOG guidelines—even small gifts and meals designed to influence physician’s behavior; gifts should benefit patients or be related to work; no cash gifts; samples may influence prescribing behavior inappropriately; Pharmaceutical Research and Manufacturers of America (PhRMA)—no more reminder items or textbooks; modest meals presented in office or hospital permissible if accompanied by educational presentation; CME funds should be separate from marketing funds and should be given to central repository; content should be determined by CME organizers; samples acceptable

Conclusion: pharmaceutical product not associated with typical supply-and-demand relationship; consumer creates demand, but physician acts as gatekeeper; although operating in free market economy, companies have government-granted monopolies (eg, patent protection for 9-11 yr); speaker argues pharmaceutical companies should be held to higher sense of social responsibility than manufacturers of other commodities; unbiased alternatives—publications such as The Medical Letter, Physician’s Desk Reference (PDR), and online resources (eg, Micromedex, Epocrates, Uptodate) educate trainees to deal with industry; institutions promoting academic detailing programs (health professionals [eg, pharmacists, nurses], rather than pharmaceutical representatives, educate peers on new drugs); clinical trials registry; disclosure laws enacted in some states; some major academic medical centers have accepted policy proposal outlining how institutions can eliminate COI; no adverse consequences to patient care or education reported