Toxic Chemicals in the Daily Environment

Reducing Chronic Diseases and Disorders

Through Safer Solutions

Ted Schettler MD, MPHScience and Environmental Health Network

www.sehn.org

environment

Poverty

Racism

Stress

Access to health care

Social support

Nutrition Toxic chemicalsRadiationInfectionsPhysical agents

genesGenes and environment are in continuousconversation

Environmental factors can altergene function, gene expression

Health

Status of Developmental Toxicity Testingfor the 2,863 Chemicals

Produced Above 1 million pounds/year

21.4%

0.4%

78.2%

No DataOn DevelopmentalToxicity

~ 30 Tested for NeurodevelopmentalToxicityAccording to EPAGuidelines

Some DataOn DevelopmentalToxicity

In Harm’s Way, www.preventingharm.org

Chemicals in consumer products

• Many different potential health effects; e.g. asthma; cancer; birth defects; altered fetal, infant, child, development; infertility, etc.

• Level, timing, duration of exposure are important; windows of vulnerability

• Susceptible sub-populations for a variety of reasons; e.g. multiple, cumulative exposures; associated stressors; life stage; genetic determinants, etc.

This presentation

• Focus on one chemical (bisphenol A) used in many different consumer products– An example of a more general set of issues– Ubiquitous exposures– Increasingly well studied; instructive with respect

to toxic properties

• Policy implications and options

Bisphenol A

• First synthesized in late 19th century

• Determined to be estrogenic in 1920s

• Polymerized in polycarbonate plastic and also used in some resins and flame retardants

• Annual global production > 6 billion pounds

Bisphenol A uses• food and drink packaging; • CDs and other hard plastics• lacquers that coat metal products such as food cans,

bottle tops, and water supply pipes. • polyester resins, polysulfone resins, polyacrylate resins,

flame retardants. • processing of polyvinyl chloride plastic and in the

recycling of thermal paper. • Some polymers used in dental sealants and tooth

coatings contain bisphenol A

Bisphenol A—exposures

• Widespread in general population– 93% of representative study population have

detectable levels of BPA in urine (NHANES, included no children less than 6 yrs old)

– Levels higher in children than adults

– Male median 1.63 ng/ml urine– Female median 1.12 ng/ml urine

Bisphenol A--exposures

• Childhood exposure estimates:– Most studies estimate 2-20 microgm/kg/day from

dietary sources for infants and young children(CERHR, 2008)

Bisphenol A metabolism• Bisphenol A absorbed from intestinal tract• Metabolism involves glucuronidation, which

renders the BPA less active and facilitates excretion

• A debate about the speed with which this occurs and whether free BPA is in the blood has been featured in scientific literature

• Fetus and infant have undeveloped glucuronidation capacity

Bisphenol A at ‘everyday levels’

Human, (free BPA)

BPA in blood and breast milk

CERHR, Natl Toxicol Program, 2008

Fig. 2. Concentrations (in ng/ml) of unconjugated BPA in plasma in femalemouse pups throughout the 24 h after a single dose, administered either orally(solid line) or by subcutaneous injection (dashed line). BPA was administeredat either 35microg/kg (low dose, circles) or 395microg/kg (high dose, squares). Valuesrepresent mean plasma values at each time point (±S.E.M.). Note the log scalefor the Y-axis. (Taylor et al. Repro Toxicology, 2008)

Bisphenol A—toxicity

• Estrogenic activity through classic estrogen receptor has received considerable attention

• We now know that BPA can also act through other receptors and other mechanisms, including modifying thyroid hormone status

• Concentrate here on low dose effects

Health questions about BPA

Aneuploidy: Down’s

Prostate, breast cancer

Impaired brain development

Long-term memory formation

Obesity and diabetes

Low sperm count

Dementia

Hyperactivity

BPA—breast cancer

• Peri-natal exposure to environmentally relevant doses of BPA (subcutaneously)—mice

• Female offspring with increased number of terminal end buds in mammary glands and decreased apoptosis (programmed cell death); intraductal hyperplasia

Vandenberg et al; Repro Toxicol; 2008Munoz-de-Toro; Endocrinology; 2005

BPA—breast cancer

• Mice—neonatal and pre-pubertal exposure to BPA via lactation resulted in increased numbers and shorter latency of tumors in mammary glands of female offspring after exposure to a carcinogen (DMBA) in adulthood

• Various proteins associated with cell proliferation and decreased apoptosis upregulated in adults (Jenkins, EHP, 2009)

BPA—prostate cancer

• Mice—prenatal exposure to environmentally relevant doses of BPA causes proliferation of ducts and prostatic intraepithelial neoplasia in male offspring

• Rats—perinatal exposure to BPA increases precancerous lesions and susceptibility to hormonally related adult prostate cancer (Prins, 2008)

BPA--aneuploidy

• Mice—low level BPA exposure interferes with chromosomal separation during cell division resulting in aneuploid cells (abnormal numbers of chromosomes in daughter cells)

(Hunt, Curr Biol, 2003)

Aneuploidy… cell division gone wrong

Bisphenol A causes aneuploidy

Bisphenol A causes insulin resistance in mice

Rapid response:Rapid response:30 min after addition of 30 min after addition of

BPA or estradiol:BPA or estradiol:Blood sugar drops becauseBlood sugar drops because

insulin increasedinsulin increased

Slower response:Slower response:After 4 days BPA-treatment, After 4 days BPA-treatment,

insulin increases but animals no insulin increases but animals no longer respond longer respond

Alonso-Magdalena; EHP, 2006Ropero, Intl J Androl, 2008

Bisphenol A—diabetes, humans

• Higher BPA concentrations were associated with diabetes (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.21-1.60; P < .001)

NHANES population-wide survey(Lang et al.; JAMA; 2008)

Bisphenol A—heart disease, human

• Higher urinary BPA concentrations were associated with cardiovascular diagnoses in age-, sex-, and fully adjusted models (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.18-1.63; P = .001 with full adjustment).

NHANES; representative population(Lang, et al.; JAMA; 2008)

Bisphenol A suppresses adiponectin release from human adipose tissue (in vitro explants); Adiponectin is a hormone that protects against insulin resistance, metabolic syndrome, inflammation.

Hugo, Environ Health Perspect; 2008

Bisphenol A—brain • Many studies of developmental exposures to

BPA in rodents and impacts on behavior– Decreased response to novelty; increased general

activity in females – in all different experimental settings, while a

significant sex difference was observed in the control group, exposure to BPA decreased or eliminated the sex difference in behavior

– Associated with altered levels of neurotransmitters in sexually dimorphic brain

areas (Palanza; Environ Res, 2008)

Bisphenol A—brain • exposure of

ovariectomized young adult nonhuman primates to BPA at 50 microg/kg/d

completely abolishes the synapse-forming effect of estradiol in all hippocampal subregions (memory, learning)

Leranth, PNAS, 2008

CERHR—Natl Toxicology Program

• The NTP has some concern for effects on the brain, behavior, and prostate gland in fetuses, infants, and children at current human exposures to bisphenol A.

CERHR, Natl Toxicology Program, 2008

Conclusion• Multiple lines of evidence show that BPA is

causally associated with and correlates with a number of health effects of concern to humans at current exposure levels

• Virtually the ENTIRE human population is exposed• From a public health perspective, this means that

the entire population is at risk• Even if the additional risk from BPA is small for

any given endpoint, the public health implications are highly significant

Taking action

• Goal: Protect public health; primary prevention

• Choose between false positive vs. false negative errors (who decides?)

• Locate the burden of proof in the system• Seek and implement safer alternatives• Reduce uncertainties by pre-market safety

testing of chemicals and materials; e.g REACH in the EU