Natural Medicine Journal Environmental Medicine Special Issue 2015 by Diversified Communications

SEPTEMBER 2015 SUPPLEMENT

SPECIAL ISSUE

Environmental Medicine

Air Pollution, Disease, and Mortality Toxic Metal Exposure: Interview With Robin Bernhoft, MD, FACS BPA in Pregnant Women

Pregnancy Complications in Manicurists Low-dose Chemical Mixtures as Carcinogens Air Pollution Aggravates Diabetes

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SPECIAL ISSUE ENVIRONMENTAL MEDICINE SEPTEMBER 2015 VOL 7, NO. 91 (SUPPL)

Contents

PEER-REVIEWED ARTICLE

Air Pollution, Disease, and Mortality

SPONSORED PODCAST

Exploring Bio-detoxification With Russell Jaffe, MD, PhD

AUDIO INTERVIEW

Health Implications of Toxic Metal Exposure With Robin Bernhoft, MD, FACS

ABSTRACTS & COMMENTARY

18 Does Air Pollution Make Women Anxious? 20 Bisphenol A and Pregnant Women 22 Are Cosmetologists and Manicurists at Greater Risk for Pregnancy Complications? 27 Low-dose Chemical Mixtures as Carcinogens 29

Air Pollution Aggravates Diabetes

Contributors WALTER J. CRINNION, ND, received his doctorate in naturopathic medicine from Bastyr University, Seattle, Washington, in their first graduating class. Crinnion has been on the board of directors of the American Association of Naturopathic Physicians and has Walter J. Crinnion, ND twice received their award for in-office research. He has been a faculty member at Bastyr University; the National College of Naturopathic Medicine, Portland, Oregon; the University of Bridgeport School of Naturopathic Medicine, Connecticut; and Southwest College of Naturopathic Medicine, Tempe, Arizona, where he chaired the environmental medicine department. He is now the chief science officer at Enzymedica, Venice, Florida.

ANNE MARIE FINE, NMD, graduated from the Southwest College of Naturopathic Medicine (SCNM), Tempe, Arizona, and now practices in Newport Beach, California. She has completed the postgraduate certification course in environmental medicine through SCNM. Anne Marie Fine, Fine serves on the board of directors of NMD the Naturopathic Association of Environmental Medicine. She has published numerous articles in peer-reviewed journals and lectures frequently in the area of epigenetics and environment. She is also the founder and chief executive officer of Fine Natural Products, LLC, a company dedicated to formulating clean and nontoxic skin care products.

JULIANNE FORBES, ND, attended the State University of New York at Oneonta where she studied chemistry and business economics and the University of New Hampshire where she obtained a master’s degree in business administration. She received her Julianne Forbes, doctorate of naturopathic medicine ND from National College of Natural Medicine, Portland, Oregon, and is a member of the Maine Association of Naturopathic Physicians and the American Association of Naturopathic Physicians. Visit her website, www.mainenaturopath.net, for more information.

TINA KACZOR, ND, FABNO, is editor in chief of Natural Medicine Journal and a naturopathic physician, board certified in naturopathic oncology. She received her naturopathic doctorate from National College of Natural Medicine, Portland, Oregon, and completed her residency in naturopathic oncology at Tina Kaczor, ND, Cancer Treatment Centers of America, Tulsa, FABNO Oklahoma. Kaczor earned undergraduate degrees from the State University of New York at Buffalo. She is the past president and treasurer of the Oncology Association of Naturopathic Physicians and secretary of the American Board of Naturopathic Oncology. She has been published in several peer-reviewed journals. Kaczor is based in Eugene, Oregon. JACOB SCHOR, ND, FABNO, is a graduate of National College of Naturopathic Medicine, Portland, Oregon, and now practices in Denver, Colorado. He served as president of the Colorado Association of Naturopathic Physicians and is now on the board of directors of both the Oncology Association of Jacob Schor, ND, Naturopathic Physicians and the American FABNO Association of Naturopathic Physicians. He is recognized as a fellow by the American Board of Naturopathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR), and Integrative Medicine: A Clinician’s Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal.

Jessica Tran, ND

JESSICA TRAN, ND, is a doctor of naturopathic medicine with special emphasis on the impact of environmental factors on the human body. Tran provides science-based natural medicine for the prevention and treatment of common and chronic illnesses for Wellness Integrative Naturopathic Consulting, Inc, Irvine, California, and in her practice in Scotts dale, Arizona.

EDITOR IN CHIEF Tina Kaczor, ND, FABNO ASSOCIATE MEDICAL EDITOR Jacob Schor, ND, FABNO PUBLISHER Karolyn A. Gazella VP, CONTENT & COMMUNICATIONS Deirdre Shevlin Bell ASSOCIATE EDITOR Anne Lanctôt DESIGN Karen Sperry PUBLISHED BY IMPACT Health Media, Inc. Boulder, Colorado Natural Medicine Journal (ISSN 2157-6769) is published 14 times per year by IMPACT Health Media, Inc.. Copyright © 2015 by IMPACT Health Media, Inc.. All rights reserved. No part of this publication may be reproduced in whole or in part without written permission from the publisher. The statements and opinions in the articles in this publication are the responsibility of the authors; IMPACT Health Media, Inc. assumes no liability for any information published herein. Advertisements in this publication do not indicate endorsement or approval of the products or services by the editors or authors of this publication. IMPACT Health Media, Inc. is not liable for any injury or harm to persons or property resulting from statements made or products or services referred to in the articles or advertisements.

MESSAGE FROM THE PUBLISHER

Addressing Environmental Toxicity is More Important Than Ever The Environmental Protection Agency reports that each year, 700 new chemicals are added to the existing 84,000+ chemicals already in our lives. Of those, about 3,000 are produced or imported in volumes greater than one million pounds per year. In 2011, Vogel and Roberts reported in the journal Health Affairs that most of these chemicals enter the marketplace without comprehensive research into their toxic effects and that we need to overhaul and strengthen oversight of chemicals beyond the outdated Toxic Substances Control Act of 1976. There is no question that we live in a toxic environment and patients—especially those who are most vulnerable and susceptible—are paying a significant price when it comes to their health. And yet treating environmentally related toxicity is something that very few conventional medical physicians understand or embrace. This treatment gap is being expertly filled by integrative practitioners who have done advanced training in the area of environmental medicine. Diagnosing and treating environmentally related illnesses can be complex, but integrative health practitioners are uniquely poised to address and prevent them. We hope you find this issue interesting and that the information helps you address this important topic in your patients. A special thanks to this issue’s guest editor, our very own Jacob Schor, ND, FABNO, for all of his hard work on this edition of the Natural Medicine Journal. In good health,

Karolyn A. Gazella

PEER-REVIEWED ARTICLE

Air Pollution, Disease, and Mortality Particulate matter as a global health threat

By Walter Crinnion, ND

ABSTRACT The World Health Organization has stated that air pollution accounts for 1.3 million deaths worldwide every year. This article reviews the association of air pollutants with all major causes of death. With those associations understood, it becomes clear that outdoor air pollution is likely to be an even greater cause of mortality across the globe than is currently recognized.

INTRODUCTION The World Health Organization (WHO) has stated that air pollution accounts for 1.3 million deaths worldwide every year.1 Upon a review of the WHO listing of the leading causes of death (Table 1), one will see that deaths from outdoor air pollutants come in just between tuberculosis and diabetes mellitus.2 This article will review the association of air pollutants with all the major causes of death listed below except diarrheal diseases, HIV/AIDS, tuberculosis, and traffic accidents. Once those associations are understood, outdoor air pollution appears likely to be an even greater cause of mortality across the globe than is currently recognized. AIR POLLUTANTS Outdoor air is contaminated with a host of vapors, gases, and particulates from combustion (vehicular, industrial, stationary, and natural sources), evaporation, industry, agriculture, and other daily activities during which these substances become airborne. Indoor air has all the same pollutants, to which are added additional toxicants from building materials, furnishings, cooking, cleaning chemicals, and air fresheners, to name a few, making indoor air pollution potentially worse than outdoor.

Deaths in Millions

% of Deaths

Ischemic heart disease

7.25

12.8

Stroke

6.15

6.4

Lower respiratory infection

3.46

6.1

Chronic obstructive pulmonary disease

3.28

5.8

Diarrheal diseases

2.46

4.3

HIV/AIDS

1.78

3.1

Respiratory-tract cancers

1.39

2.4

Tuberculosis

1.34

2.4

Diabetes mellitus

1.26

2.2

Traffic accidents

1.21

2.1

Table 1. Major Causes of Death Compiled From World Health Organization Statistics1

URBAN AIR POLLUTION LEVELS The major population centers have the greatest amount of air pollutants, mostly due to stationary energy sources and industry, as well as the huge amount of fuel burned to provide transportation. Because of the multiple health problems posed by such pollution, the United States Congress passed the Clean Air Act in 1970, which allowed the federal government to set limits for emissions from stationary and mobile sources of pollution. In May 1971, the Environmental Protection Agency (EPA) was established to implement the mandates of the Clean Air Act. Since 1970, the Clean Air Act has been amended twice (in 1977 and in 1990).3 Part of the original 1970 mandate allowed the newly formed EPA to set national ambient air quality standards for various pollutants. The EPA chose the 6 most common and most damaging pollutants, which are also referred to as “criteria pollutants.” These are particle pollution (often referred to as particulate matter [PM]), ground-level ozone, carbon monoxide, sulfur oxides, nitrogen oxides, and lead. Of the 6 pollutants, particle pollution and ground-level ozone pose the most widespread health threats. These 6 are called criteria air pollutants because their permissible levels are derived from either human health-based and/or environmentally based criteria (science-based guidelines). These criteria are referred to as “primary” when they

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are based on human health outcomes and “secondary” when they are associated with environmental or property damage.4

the greatest exposure to UFPs but rather the urban background levels. The activities that were associated with the greatest exposure to UFPs were outdoor activities (exposure to ambient urban air), cooking and eating in the home, and commuting.

While all of these 6 criteria pollutants deserve attention, this article will focus on PM, the aromatic hydrocarbons it carries, and the illnesses associated with it. UFPs are small enough to enter the bloodstream and settle in more distant organs than the lungs. For example, UFP PARTICULATE MATTER levels in the livers of rats 18 to 24 hours after UFP expoPM is a combination of liquid droplets (aerosols) and solid sure were found to be 5 times higher than the PM levels in 9 particles like dust, soot, smoke, and dirt. Particulates are found their lungs. These UFPs can also travel from the nose into 10 in smoke, diesel exhaust, and haze that either come directly the brain via the olfactory nerve. UFPs of iron oxide, India from combustion or are products of a reaction between gases ink, and titanium dioxide that were initially identified in and sunlight or air. From a health perspective, PM is differen- alveolar macrophages were found a day later in the lung (in tiated according to particle size.5 The largest of the PM, called the highest concentration), liver, kidney, heart, tracheobroncoarse particles, are between 10 mm and 2.5 mm and are chial and mediastinal lymph nodes, anterior and posterior given the designation of PM10. These are often encountered nasal cavity, the brain, and the blood. At 4 days postexponear dusty roadways and industry. They are known to lodge sure, particles were found in all of the above except for the in the trachea or bronchi. Fine particles are those between 2.5 nasal cavity and brain. At 7 days postexposure, they were still 11 mm and 0.1 mm in diameter and are designated as PM2.5. found in the lungs, liver, and blood. A group of rats that Fine particles can lodge in the alveoli of the lungs. Ultrafine were exposed only once to UFPs and then sacrificed after particles (UFPs), also called nanoparticles, are less than 0.1 either 3 weeks, 2 months, or 6 months showed that the UFP mm (100 nm) in size (PM<0.1). Concentrations of atmo- concentrations in the brain, heart, spleen, liver, and lungs spheric UFPs are tens of thousands of times higher in urban from the single exposure slowly reduced over time, with the 12 air than in rural air and are considered the most detrimental lungs retaining the most UFP. Of course, urban-dwelling humans are exposed daily and are not allowed time to clear of all PM fractions.6 the UFP from their organs. UFPs can be either exhaled or absorbed systemically. Absorption of UFPs can pose serious health risks. For example, UFPs cause significant oxidative damage in the tissues and 13-15 traffic exhaust UFPs are associated with adverse effects in the organs to which they are distributed. PM in general has respiratory, cardiovascular, and nervous systems, in addition been associated with increased mortality primarily from 16,17 18 19 to stimulating oxidative damage and inflammation.7 The 2 cardiovascular, respiratory, and neoplastic diseases. PM major sources of UFPs are cigarette smoke and diesel exhaust; of all sizes act as carriers for a number of other potent air biodiesel puts out even higher UFP levels than regular diesel.8 pollutant chemicals, including polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs), which A recent study in Australia sought to find out where children may account for some of their toxic health effects.20 encountered their highest exposures to UFPs. The researchers were initially quite concerned about diesel-powered school POLYCYCLIC AROMATIC HYDROCARBONS buses that often idle outside the school at the end of the school PAHs are highly lipophilic (fat soluble) and therefore are day.6 They discovered that the greatest exposure to UFPs was found naturally in oil, coal, and tar deposits. They are also actually encountered at home (55% of the total daily exposure), found in the consumer products coal tars, crude oils, creowith school exposure being the second highest source (35% of sote, and roofing tar. More than 100 PAHs are formed during the total). Interestingly, it was not the idling buses that provided the incomplete burning of coal, oil, and gas for fuels; the NMJ, SEPTEMBER 2015 SUPPLEMENT—VOL. 7, NO. 91 (SUPPL) ©2015 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. 7

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incineration of garbage; smoking tobacco; or the charbroiling The table shows that diesel exhaust is a major source of of meat. In short, the burning of anything that is carbon- the most common PAHs, including those that are known based may produce PAHs. (benzo[a]pyrene) or probable carcinogens. Benzo[a]pyrene is metabolized by cytochrome P450 1A2 and transformed Table 2 lists the 17 most common PAHs as well as their carci- into a far more toxic metabolite: benzo[a]pyrene epoxide, nogenic rating by the EPA and whether each is present in highly carcinogenic.26 diesel exhaust. The EPA has determined that benz[a]anthracene, benzo[a]pyrene, benzo[b]fluoranthene, benzo[k]fluoran- INDUSTRIAL- AND VEHICLE-GENERATED thene, chrysene, dibenz[a,h]anthracene, and indeno[1,2,3-c,d] VOLATILE ORGANIC COMPOUNDS pyrene are probable human carcinogens.21Benzo[a]pyrene is a Volatile Organic Compounds (VOCs), also referred to as known human carcinogen and is the main lung carcinogen solvents, are typically short-chain hydrocarbons that evapin cigarette smoke22 and vehicular exhaust.23 Both PM and orate rapidly at ambient temperatures and have a variety PAHs are known to damage mitochondria and suppress their of industrial uses.27 VOCs are used in paints, glues, inks, proper functioning.24,25 fragrances, and building materials and are found in cigarette smoke, gasoline, and vehicular exhaust. The 4 most Probable common VOCs are benzene, toluene, ethylbenzene, and Polycyclic Aromatic Carcinogens per Present in Diesel Hydrocarbons US Environmental Exhaust xylene; they are often referred to simply as BTEX and can Protection Agency account for up to 27% of each gallon of gas dispensed at Acenapthene the pump for every vehicle.28 For the United States as a Acenapthylene X whole, vehicular emissions are the greatest source of these Anthracene X compounds found in urban and rural air, but in areas of the country where refineries and chemical plants are located, Benz[a]anthracene X X these nonmobile sources far surpass emissions put out by Benzo[a]pyrene X X transport vehicles. The EPA website provides information Benzo[e]pyrene X on the total VOC emissions for the entire United States or Benzo[b]flouranthene X X by state or county.

Benzo[j]flouranthene

Benzo[k]flouranthene

Benzo[g,h,i]perylene

Chrysene

Dibenzo[a,h] anthracene

Flouranthene

Flourene

Indeno[1,2,3-cd] pyrene

Phenanthrene

Pyrene

Table 2. The 17 Most Common Polycyclic Aromatic Hydrocarbons in

Data from the 1990 US EPA Cumulative Exposure Project looked at 148 toxic air contaminants for each of the 30,803 census tracts in the contiguous United States.29 Concentrations of benzene, formaldehyde, and 1,3-butadiene were greater than levels known to cause cancer (cancer benchmark levels) in over 90% of the census tracts. Approximately 10% of the census tracts had 1 or more carcinogenic hazardous air pollutant in concentrations above 1-in-10,000 risk levels. As an example, these data revealed that of 25 sites in Minnesota, 10 pollutants were found that exceeded the benchmarks in 1 or more sites (acrolein; arsenic; benzene; 1,3-butadiene; carbon tetrachloride; chromium; chloroform; ethylene dibromide; formaldehyde; and nickel).30

Outdoor Air

(continued on page 10)

1 se ls ly a e al re ev ic inc e l n lin C d to hio i e t at ud lu st d g

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The Brookhaven Medical Unit in Atlanta, Georgia, an environmentally controlled clinic, has filters of activated charcoal and aluminum oxide impregnated with potassium permanganate to rapidly eliminate fumes and provide less-polluted air for those in the clinic. Yet even in such a tightly controlled unit, at times of peak traffic flow, levels of hydrocarbons, and other exhaust components (carbon monoxide, chlorine dioxide, hydrogen cyanide, nitrogen dioxide, and ozone) were detected in the unit.31

across the globe, within 2 days of increased PM levels, the mortality rates increase.33,34 Recent estimates show that aggressive reductions in global PM production could reduce global annual mortality rates attributed to PM2.5 by 23%.35

CARDIOVASCULAR DISEASE Many of the deaths associated with higher levels of PM are directly due to acute myocardial infarctions (MI), to which PM is strongly linked. An article in the New England Journal of Medicine in 2004 reported that an association was found A study of cyclists in an urban area showed elevated serum between exposure to traffic and the onset of a MI within benzene and toluene and elevated toluene and xylenes in the 1 hour of beginning their morning commute (odds ratio: urine after a 2-hour ride. Those riding in urban areas had 2.92).36 The authors attribute at least some of this increase consistently higher post-ride levels of these compounds than to vehicular exhaust exposure. Six years later, Circulation, the those riding in rural areas (details summarized in Table 3).32 official journal of the American Heart Association, published Health problems associated with vehicular exhaust include a statement saying that there is an established causal relationto PM2.5 and cardiovascular morbidity increased mortality, cardiovascular illness, respiratory illness, ship between exposure 37 and mortality. This group also noted that reductions in PM neurological problems, and endocrine disorders including exposure were associated with reduced rates of cardiovascular obesity, diabetes, and infertility. mortality within just a few years’ timeframe: MORTALITY Exposure to PM<2.5µm (PM2.5) over a few hours to weeks PM, with its attached load of PAH and VOCs, has long can trigger cardiovascular disease-related mortality and been associated with a number of adverse health outcomes, nonfatal events; longer-term exposure increases the risk for including increased mortality. In studies done in major cities cardiovascular mortality to an even greater extent than exposures over a few days and reduces life expectancy within the Rural Rides Urban Rides more highly exposed segments of the population by several (blood ng/L) (blood ng/L) months to a few years.37 Benzene Toluene Ethylbenzene Xylenes Benzene Toluene Ethylbenzene Xylenes

Pre-ride 190.0 310.1 232.0 735.0

Post-ride 188.9 320.2 237.0 697.3

Rural Rides (urine ng/L)

Pre-ride 127.6 282.0 82.8 210.4

Post-ride 112.4 280.1 86.1 219.0

Pre-ride 186.1 310.3 239.0 831.4

Post-ride 224.2 436.3 292.5 1190.0

Urban rides (urine ng/L)

Pre-ride 104.2 295.1 70.1 220.3

Post-ride 120.5 338.3 74.5 251.1

Table 3. Data From Bergamaschi et al: “Bicyclist Biomarkers of Internal Dose in Pre-ride and Post-ride Blood and Urine Samples”32

Yet even with this clear statement by the American Heart Association, the use of measures to reduce PM exposure to prevent the number 1 killer of Americans today has received little or no public exposure. Carotid intima-media thickness (CIMT) is used as an easily assessed surrogate marker for atherosclerosis and is a strong predictor of future cardiovascular events.38 Each standard deviation increase in CIMT is associated with a 32% increased risk of stroke and a 26% increased risk of MI. In a large study of almost 6,000 adults from 6 different US communities, it was noted that people living with higher home air PM2.5 (from both outdoor and indoor sources) had far greater CIMT

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progression than those with lower PM2.5 exposure.39 These data corroborated a prior study of adults living in the Los Angeles, California, basin that showed air pollution is associated with progression of atherosclerosis via CIMT testing.40

tory disease in those living close to busy roadways vs those who live farther from main thoroughfares. All such studies have confirmed that the closer one is to a higher level of vehicular exhaust (especially diesel truck exhaust), the greater the risk of asthma.52,53 One of the largest studies to date to explore CIMT has been directly linked with PAH levels as well. A the association between air pollution and respiratory disease study of Brazilian cab drivers and non‒cab driving controls is the European Study of Cohorts for Air Pollution Effects measured 1-hydroxypyrene (1-OHP), a common metabolite project, which encompasses 10 European birth cohorts in of traffic-related PAH compounds and a validated marker 6 countries with a total of 16,059 children.54 The authors for PAH exposure, along with other indices of cardiovascular found that exposure to air pollution clearly increased the risk inflammation and disease.41 The taxi drivers had significantly of pneumonia in the children they followed. higher levels of 1-OHP along with higher levels of oxidized low-density lipoprotein (LDL), homocysteine, high-sensitivity While respiratory and cardiovascular effects of air pollution c-reactive protein, and other proinflammatory cytokine have long been associated with mortality, recent studies are markers. The researchers also reported that the taxi drivers linking it to a number of other issues, including neurological had significantly lower levels of glutathione peroxidase and and endocrine issues. glutathione transferase function, as well as lower levels of NEUROLOGICAL EFFECTS ascorbic acid. This group of researchers then took the study 1 Exposure to vehicular exhaust has been clearly linked to step further and looked at the level of atherosclerosis that was reduced cognitive functioning in both children and adults. In present in the drivers and controls to see how that related to all adults, it has been associated with depression, and in children, of these other markers.42 This was the study in which 1-OHP it may influence the risk and severity of autistic spectrum was directly linked with not only serum homocysteine levels, disorder. Prenatal exposure to PAH compounds from vehicbut also greater CIMT. Interestingly, the CIMT was not assoular exhaust leads to reduced intelligence quotient (IQ) levels ciated with total cholesterol, triglycerides, or LDL levels. in children. An ongoing study in New York City has been Hypertension is a major risk factor for both stroke and heart following a birth cohort of 249 children whose mothers were attack, as well as increased morbidity to other organs in the body; assessed for PAH exposure with personal air monitors during it is also clearly associated with air pollution levels.43 Long-term their third trimester. By the age of 3, the children whose exposure to elevated levels of all PM sizes leads to an elevation in mothers had median or higher levels of PAH exposure showed 55 diastolic blood pressure in both adults and children.44,45 Inter- developmental delay. By the age of 5, these same children estingly, this effect is heightened in people who are obese46 and showed full scale IQ and verbal IQ levels that were signifiwho are psychologically stressed,47 while the effect is reduced cantly lower than children with lower prenatal PAH exposure 56 in those children who were breastfed.48 Not only can vehicular (P=0.009). A similarly designed study in Krakow, Poland, exhaust particulate matter levels increase diastolic blood pres- also measured mothers’ PAH exposure and found similar IQ sure, but biological PM49 (commonly found in indoor air) and point loss in the 5-year-old children who had greater prenatal PAH exposure.57 The researchers who followed the cohort the use of biomass fuel can do the same.50 in New York later published their estimate of the economic RESPIRATORY ILLNESS effects on these 249 children based on their lifetime earning It has long been established that children have far higher if a modest reduction in PAH could be achieved. Their rates of asthma, bronchitis, bronchiolitis, pneumonia, published finding proposed that a mere 0.25 ng/m3 reduction phlegm production, and wheezing when exposed to vehicular of PAHs, achievable by good indoor air purification, would exhaust.51 Several studies have looked at the rates of respira- boost the lifetime earnings of the cohort by $215 million.58 NMJ, SEPTEMBER 2015 SUPPLEMENT—VOL. 7, NO. 91 (SUPPL) ©2015 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. 11

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A number of convincing studies have also been published revealing the association between vehicular exhaust and both rates and severity of autism. Children who were gestationally exposed to high levels of vehicular exhaust were twice as likely to be autistic as those who had lower exposures, while those with higher exposure during the first year of life had triple the risk.59 The closer the mothers-to-be lived to a freeway, the higher the risk for having an autistic child.60 Subsequent studies have found that exposure to vehicular exhaust during the first and second trimesters do not increase the risk, but exposure during the third trimester does.61,62 Diesel exhaust turned out to be the greatest exhaust-source risk for the development of autism in the Children of Nurses’ Health Study II.63 The effect of PM on cognition in adults was the focus of a study that involved the 19,409 women in the Nurses’ Health Study Cognitive Cohort. These women ranged in age from 70 to 81 years, and their cognitive measurements were correlated with PM (both PM10 and PM2.5) levels.64 They found that women who were exposed to higher levels of both PM10 and PM2.5 for 7 to 14 years had significantly faster cognitive decline as they aged. The researchers were actually able to quantify the cognitive decline in relation to the levels of PM, showing that an increase of 10 µg/m3 of long-term PM 2.5 exposure resulted in the same reduction in cognition as would occur from 2 years of aging in those between the ages of 70 and 81 years. A similar result was reported by a group of researchers who used data from the US Department of Veterans Affairs Normative Aging Study.65 This group of males with an average age of 71 years had been administered cognitive testing 7 times during an 11-year period while levels of black carbon were used as a marker for vehicular exhaust. The researchers reported that for every doubling of the ambient levels of black carbon, the participants experienced a cognitive decline that was equivalent to 1.9 years of aging. In addition to cognitive decline, 2 studies have now clearly linked urban air pollution to increased risk of depression.66,67

population. Italian traffic policemen who were exposed daily to vehicular exhaust throughout their shifts had significantly lower levels of free testosterone than police assigned to other duties.68 Exposure to vehicular exhaust and cigarette smoke are also strongly associated with multiple sperm abnormalities associated with male infertility.69-71 Similarly, exposure to vehicular exhaust is also associated with increased female infertility rates.72 In infertile couples who have chosen to undergo in vitro fertilization, PM exposure during the preconception period also greatly increases risk of pregnancy loss.73 Children exposed to higher levels of vehicular air pollutants were up to 3 times more likely to develop type 1 diabetes than children breathing air with lower levels of vehicular exhaust compounds.74 In this study, the highest diabetes risk came from exposure to high levels of ozone derived from traffic sources. In a group of almost 400 German 10-year-olds, exposure to vehicular exhaust increased their incidence of insulin resistance, one of the first steps to developing type 2 diabetes.75 Long-term exposure to vehicular PM has also been directly associated with higher risk in adults for developing both metabolic syndrome and type 2 diabetes.76,77 Exposure to high levels of PM2.5 during the second trimester of pregnancy gave women a far higher risk of developing impaired glucose tolerance during pregnancy.78 Women with the highest PM2.5 exposure levels and with the closest proximity of heavy traffic were 2.6 times more likely to have problems with their blood sugar levels, although no direct link was found between vehicular exhaust and the risk of overt gestational diabetes mellitus.

As mentioned previously, PM from vehicular exhaust is known to lead to increased risk of the development of metabolic syndrome, one of whose manifestations is increased body weight. PAHs from urban air and from environmental tobacco smoke (ETS) are both associated with hugely increased risk levels for childhood obesity. Using data from the 2003-2008 National Health and Nutrition Examination Survey, researchers found that children in the second, third, and fourth quintiles of urinary PAH metabolites had ENDOCRINE EFFECTS risk factors for obesity that were 4.51, 2.57, and 8.09 times Urban air pollution has been linked to increased risk of infer- greater, respectively, than those in the lowest quintile.79 For tility, obesity, and diabetes, all common problems in the modern (continued on page 14) 12 ©2015 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, SEPTEMBER 2015 SUPPLEMENT—VOL. 7, NO. 91 (SUPPL)

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the children exposed to both the higher PAH levels and ETS, the levels went up even higher, showing a clear synergistic effect leading to far greater body mass index in these children. CONCLUSION Air is vital for human life, with the average adult inhaling more than 17,000 times every day. Unfortunately, with very few exceptions, each of those daily breaths may come with a substantial number of toxicants with severe health consequences. In fact, adverse health effects of air pollutants include cardiovascular disease, which is the most common cause of death in North America. These same air pollutants are associated with a variety of adverse respiratory, neurological, hormonal, and cognitive effects; they also increase a woman’s risk of having an autistic child. Much more focus needs to be placed on recognizing the important role that common air pollutants hold in health, with commensurate actions being taken to reduce the levels of common air pollutants in the home—the one environment most people are in control of. It is quite possible that one of the most effective preventive medicine modalities would be the installation of a high-quality air purifier in the home. REFERENCES 1 World Health Organization. The top 10 causes of death. Available at: http://www.who. int/mediacentre/factsheets/fs310/en/. Accessed August 31, 2015. 2 World Health Organization. Ambient (outdoor) air quality and health. Available at: http:// www.who.int/mediacentre/factsheets/fs313/en/. Accessed August 31, 2015. 3 US Environmental Protection Agency. 40th anniversary of the Clear Air Act. Available at: http://www.epa.gov/air/caa/40th.html. Accessed August 31, 2015. 4 US Environmental Protection Agency. What are the six common air pollutants? Available at: http://www.epa.gov/airquality/urbanair/. Accessed August 31, 2015. 5 United Nations Environmental Programme. Pollutants: Particulate matter (PM). Available at: http://www.unep.org/tnt-unep/toolkit/pollutants/facts.html. Accessed August 31, 2015. 6 Mazaheri M, Clifford S, Jayaratne R, et al. School children’s personal exposure to ultrafine particles in the urban environment. Environ Sci Technol. 2014;48(1):113-120. 7 Kumar S, Verma MK, Srivastava AK. Ultrafine particles in urban ambient air and their health perspectives. Rev Environ Health.2013;28(2-3):117-128. 8 Fukagawa NK, Li M, Poynter ME, et al. Soy biodiesel and petrodiesel emissions differ in size, chemical composition and stimulation of inflammatory responses in cells and animals. Environ Sci Technol. 2013;47(21):12496-12504. 9 Oberdorster G, Sharp Z, Atudorel V, et al. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J Toxicol Environ Health A. 2002;65(20):1531-1543. 10 Oberdorster G, Sharp Z, Atudorel V, et al. Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol. 2004;16(6-7):437-445. 11 Takenaka S, Karg E, Roth C, et al. Pulmonary and systemic distribution of inhaled ultrafine silver particles in rats. Environ Health Perspect. 2001;109 (Suppl 4):547-551. 12 Semmler M, Seitz J, Erbe R, et al. Long-term clearance kinetics of inhaled ultrafine insoluble iridium particles from the rat lung, including transient translocation into secondary organs. Inhal Toxicol. 2004;16(6-7):453-459.

13 Oh SM, Kim HR, Park YJ, Lee SY, Chung KH. Organic extracts of urban air pollution particulate matter (PM2.5)-induced genotoxicity and oxidative stress in human lung bronchial epithelial cells (BEAS-2B cells). Mutat Res. 2011;723(2):142-151. 14 Frikke-Schmidt H, Roursgaard M, Lykkesfeldt J, Loft S, Nøjgaard JK, Møller P. Effect of vitamin C and iron chelation on diesel exhaust particle and carbon black induced oxidative damage and cell adhesion molecule expression in human endothelial cells. Toxicol Lett.2011;203(3):181-189. 15 Harrison CM, Pompilius M, Pinkerton KE, Ballinger SW. Mitochondrial oxidative stress significantly influences atherogenic risk and cytokine-induced oxidant production. Environ Health Perspect. 2011;119(5):676-681. 16 Zhang P, Dong G, Sun B, et al. Long-term exposure to ambient air pollution and mortality due to cardiovascular disease and cerebrovascular disease in Shenyang, China. PLoS One. 2011;6(6):e20827. 17 Ito K, Mathes R, Ross Z, Nadas A, Thurston G, Matte T. Fine particulate matter constituents associated with cardiovascular hospitalizations and mortality in New York City. Environ Health Perspect. 2011;119(4):467-473. 18 Guaita R, Pichiule M, Maté T, Linares C, Díaz J. Short-term impact of particulate matter (PM(2.5)) on respiratory mortality in Madrid. Int J Environ Health Res. 2011;21(4):260-274. 19 Katanoda K, Sobue T, Satoh H, et al. An association between long-term exposure to ambient air pollution and mortality from lung cancer and respiratory diseases in Japan. J Epidemiol. 2011;21(2):132-143. 20 Yu JZ, Huang XH, Ho SS, Bian Q. Nonpolar organic compounds in fine particles: quantification by thermal desorption-GC/MS and evidence for their significant oxidatioin in ambient aerosols in Hong Kong. Anal Bioanal Chem. 2011;401(10):3125-3139. 21 Agency for Toxic Substances and Disease Registry. Public Health Statement for Polycyclic Aromatic Hydrocarbons (PAHs). Available at:http://www.atsdr.cdc.gov/PHS/PHS. asp?id=120&tid=25. Accessed August 31, 2015. 22 Alexandrov K, Rojas M, Satarug S. The critical DNA damage by benzo(a)pyrene in lung tissues of smokers and approaches to preventing its formation. Toxicol Lett. 2010;198(1):63-68. 23 Armstrong B, Hutchinson E, Unwin J, Fletcher T. Lung cancer risk after exposure to polycyclic aromatic hydrocarbons: a review and meta-analysis. Environ Health Perspect. 2004;112(9):970-978. 24 Xia T, Kovochich M, Nel AE. Impairment of mitochondrial function by particulate matter (PM) and their toxic components: implications for PM-induced cardiovascular and lung disease. Front Biosci. 2007 Jan 1;12:1238-1246. 25 Jiang Y, Zhou X, Chen X, et al. Benzo(a)pyrene-induced mitochondrial dysfunction and cell death in p53-null Hep3B cells. Mutat Res.2011;726(1):75-83. 26 Shimada T, Gillam EM, Oda Y, et al. Metabolism of benzo(a)pyrene to trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene by recombinant human cytochrome P450 1B1 and purified liver epoxide hydrolase. Chem Res Toxicol. 1999;12(7):623-629. 27 US Geological Survey. Volatile organic compounds (VOCs). Available at: http://toxics. usgs.gov/definitions/vocs.html. Accessed August 31, 2015. 28 Bolden AL, Kwiatkowski CF, Colborn T. New look at BTEX: Are ambient levels a problem? Environ Sci Technol. 2015;49(9):5261-5276. Epub 2015 Apr 15. 29 Woodruff TJ, Axelrad DA, Caldwell J, Morello-Frosch R, Rosenbaum A. Public health implications of the 1990 toxics concentrations across the United States. Environ Health Perspect. 1998;106(5):245-251. 30 Pratt GC, Palmer K, Wu CY, Oliaei F, Hollerbach C, Fenske MJ. An assessment of air toxics in Minnesota. Environ Health Perspect.2000;108(9):815-825. 31 Edgar RT, Fenyves EJ, Rea WJ. Air pollution analysis used in operating an environmental control unit. Ann Allergy. 1979;42(3):166-173. 32 Bergamaschi E, Burstolin A, De Palma G, et al. Biomarkers of dose and susceptibility in cyclists exposed to monoaromatic hydrocarbons. Toxicol Lett. 1999;108(2-3):241-247. 33 Peters A, Skorkovsky J, Kotesovec F, et al. Associations between mortality and air pollution in central Europe. Environ Health Perspect.2000;108(4):283-287. 34 Mar TF, Norris GA, Koenig JQ, Larson TV. Associations between air pollution and mortality in Phoenix, 1995-1997. Environ Health Perspect. 2000;108(4):347-353. 35 Apte JS, Marshall JD, Cohen AJ, Brauer M. Addressing global mortality from ambient PM2.5. Environ Sci Technol. 2015;49(13):8057-8066. Epub 2015 Jun 16. 36 Peters A, von Klot S, Heier M, et al; Cooperative Health Research in the Region of Augsburg Study Group. Exposure to traffic and the onset of myocardial infarction. N Engl J Med. 2004;351(17):1721-1730. 37 Brook RD, Rajagopalan S, Pope CA 3rd, et al; American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular Disease, and Council on Nutrition, Physical Activity and Metabolism. Particulate matter air pollution and cardiovascular disease: An update to the scientific statement from the American Heart Association. Circulation. 2010;121(21):2331-2378.

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38 Lorenz M, Markus H, Bots M, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness. A systematic review and meta-analysis. Circulation. 2007;115(4):459-467. 39 Adar SD, Sheppard L, Vedal S, et al. Fine particulate air pollution and the progression of carotid intima-medial thickness: a prospective cohort study from the multi-ethnic study of atherosclerosis and air pollution. PLoS Med. 2013;10(4):e1001430. 40 Künzli N, Jerrett M, Garcia-Esteban R, et al. Ambient air pollution and the progression of atherosclerosis in adults. PLoS One.2010;5(2):e9096. 41 Brucker N, Moro AM, Charão MF, et al. Biomarkers of occupational exposure to air pollution, inflammation and oxidative damage in taxi drivers. Sci Total Environ. 2013;463464:884-893. 42 Brucker N, Charão MF, Moro AM, et al. Atherosclerotic process in taxi drivers occupationally exposed to air pollution and co-morbidities. Environ Res. 2014 May;131:31-38. 43 Wong MC, Tam WW, Wang HH, et al. Exposure to air pollutants and mortality in hypertensive patients according to demography: a 10 year case-crossover study. Environ Pollut. 2014 Sep;192:179-185. 44 Chen SY, Wu CF, Lee JH, et al. Associations between long-term air pollutant exposures and blood pressure in elderly residents of Taipei City: a cross-sectional study. Environ Health Perspect. 2015;123(8):779-784. Epub 2015 Mar 20. 45 Dong GH, Wang J, Zeng XW, et al. Interactions between air pollution and obesity on blood pressure and hypertension in Chinese children. Epidemiology. 2015;26(5):740747. 46 Qin XD, Qian Z, Vaughn MG, et al. Gender-specific differences of interaction between obesity and air pollution on stroke and cardiovascular diseases in Chinese adults from a high pollution range area: A large population based cross sectional study. Sci Total Environ. 2015 Oct 1;529:243-248. 47 Hicken MT, Dvonch JT, Schulz AJ, Mentz G, Max P. Fine particulate matter air pollution and blood pressure: the modifying role of psychosocial stress. Environ Res. 2014 Aug;133:195-203. 48 Dong GH, Qian ZM, Trevathan E, et al. Air pollution associated hypertension and increased blood pressure may be reduced by breastfeeding in Chinese children: the Seven Northeastern Cities Chinese Children’s Study. Int J Cardiol. 2014;176(3):956961. 49 Zhong J, Urch B, Speck M, et al. Endotoxin and ?-1,3-d-glucan in concentrated ambient particles induce rapid increase in blood pressure in controlled human exposures. Hypertension. 2015;66(3):509-516. Epub 2015 Jun 29. 50 Burroughs Peña M, Romero KM, Velazquez EJ, et al. Relationship between daily exposure to biomass fuel smoke and blood pressure in high-altitude Peru. Hypertension. 2015;65(5):1134-1140. 51 Ciccone G, Forastiere F, Agabiti N, et al. Road traffic and adverse respiratory effects in children. SIDRIA Collaborative Group. Occup Environ Med. 1998;55(11):771-778. 52 Cook AG, deVos AJ, Pereira G, Jardine A, Weinstein P. Use of a total traffic count metric to investigate the impact of roadways on asthma severity: a case-control study. Environ Health. 2011 Jun 2;10:52. 53 Li S, Batterman S, Wasilevich E, Elasaad H, Wahl R, Mukherjee B. Asthma exacerbation and proximity of residence to major roads: a population-based matched casecontrol study among the pediatric Medicaid population in Detroit, Michigan. Environ Health. 2011 Apr 23;10:34. 54 Macintyre EA, Gehring U, Mölter A, et al. Air pollution and respiratory infections during early childhood: an analysis of 10 European birth cohorts within the ESCAPE Project. Environ Health Perspect. 2013;122(1):107-113. 55 Perera F, Rauh V, Whyatt RM, et al. Effect of prenatal exposure to airborne polycyclic aromatic hydrocarbons on neurodevelopment in the first 3 years of life among inner-city children. Environ Health Perspect. 2006;114(8):1287-1292. 56 Perera FP, Li Z, Whyatt R, et al. Prenatal airborne polycyclic aromatic hydrocarbon exposure and child IQ at age 5 years. Pediatrics.2009;124(2):e195-202. 57 Edwards SC, Jedrychowski W, Butscher M, et al. Prenatal exposure to airborne polycyclic aromatic hydrocarbons and children’s intelligence at 5 years of age in a prospective cohort study in Poland. Environ Health Perspect. 2010;118(9):1326-1331. 58 Perera F, Weiland K, Neidell M, Wang S. Prenatal exposure to airborne polycyclic aromatic hydrocarbons and IQ: Estimated benefit of pollution reduction. J Public Health Policy. 2014;35(3):327-336. 59 Volk HE, Lurmann F, Penfold B, Hertz-Picciotto I, McConnell R. Traffic-related air pollution, particulate matter, and autism. JAMA Psychiatry. 2013;70(1):71-77. 60 Volk HE, Hertz-Picciotto I, Delwiche L, Lurmann F, McConnell R. Residential proximity to freeways and autism in the CHARGE study.Environ Health Perspect. 2011;119(6):873877.

61 Kalkbrenner AE, Windham GC, Serre ML, et al. Particulate matter exposure, prenatal and postnatal windows of susceptibility, and autism spectrum disorders. Epidemiology. 2015;26(1):30-42. 62 Raz R, Roberts AL, Lyall K, et al. Autism spectrum disorder and particulate matter air pollution before, during, and after pregnancy: a nested case-control analysis within the Nurses’ Health Study II Cohort. Environ Health Perspect. 2015;123(3):264-270. 63 Roberts AL, Lyall K, Hart JE, et al. Perinatal air pollutant exposures and autism spectrum disorder in the children of Nurses’ Health Study II participants. Environ Health Perspect. 2013;121(8):978-984. 64 Weuve J, Puett RC, Schwartz J, Yanosky JD, Laden F, Grodstein F. Exposure to particulate air pollution and cognitive decline in older women. Arch Intern Med. 2012;172(3):219227. 65 Power MC, Weisskopf MG, Alexeeff SE, Coull BA, Spiro A 3rd, Schwartz J. Trafficrelated air pollution and cognitive function in a cohort of older men. Environ Health Perspect. 2011;119(5):682-687. 66 Cho J, Choi YJ, Suh M, et al. Air pollution as a risk factor for depressive episode in patients with cardiovascular disease, diabetes mellitus, or asthma. J Affect Disord. 2014 Mar;157:45-51. 67 Lim YH, Kim H, Kim JH, Bae S, Park HY, Hong YC. Air pollution and symptoms of depression in elderly adults. Environ Health Perspect.2012;120(7):1023-1028. 68 Sancini A, Tomei F, Tomei G, et al. Exposure to urban stressors and free testosterone plasma values. Int Arch Occup Environ Health. 2011;84(6):609-616. 69 Rengaraj D, Kwon WS, Pang MG. Effects of motor vehicle exhaust on male reproductive function and associated proteins. J Proteome Res. 2015;14(1):22-37. 70 Richthoff J, Elzanaty S, Rylander L, Hagmar L, Giwercman A. Association between tobacco exposure and reproductive parameters in adolescent males. Int J Androl. 2008;31(1):3139. 71 Rubes J, Selevan SG, Evenson DP, et al. Episodic air pollution is associated with increased DNA fragmentation in human sperm without other changes in semen quality. Hum Reprod. 2005;20(10):2776-2783. 72 Nieuwenhuijsen MJ, Basagaña X, Dadvand P, et al. Air pollution and human fertility rates. Environ Int. 2014 Sep;70:9-14. 73 Perin PM, Maluf M, Czeresnia CE, Januário DA, Saldiva PH. Impact of shortterm preconceptional exposure to particulate air pollution on treatment outcome in couples undergoing in vitro fertilization and embryo transfer (IVF/ET). J Assist Reprod Genet. 2010;27(7):371-382. 74 Hathout EH, Beeson WL, Ischander M, Rao R, Mace JW. Air pollution and type 1 diabetes in children. Pediatr Diabetes. 2006;7(2):81-87. 75 Thiering E, Cyrys J, Kratzsch J, et al. Long-term exposure to traffic-related air pollution and insulin resistance in children: results from the GINIplus and LISAplus birth cohorts. Diabetologia. 2013;56(8):1696-1704. 76 Eze IC, Schaffner E, Foraster M, et al. Long-term exposure to ambient air pollution and metabolic syndrome in adults. PLoS One.2015;10(6):e0130337. 77 Weinmayr G, Hennig F, Fuks K, et al; Heinz Nixdorf Recall Investigator Group. Longterm exposure to fine particulate matter and incidence of type 2 diabetes mellitus in a cohort study: effects of total and traffic-specific air pollution. Environ Health. 2015 Jun 19;141:53. 78 Fleisch A, Gould D, Rifas-Shiman S, et al. Air pollution exposure and abnormal glucose tolerance during pregnancy: the project viva cohort. Environ Health Perspect. 2014;122(4):378-383. 79 Kim HW, Kam S, Lee DH. Synergistic interaction between polycyclic aromatic hydrocarbons and environmental tobacco smoke on the risk of obesity in children and adolescents: The U.S. National Health and Nutrition Examination Survey 2003-2008. Environ Res. 2014 Nov;135:354-360.

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Robin Bernhoft, MD, FACS, is a former general surgeon with subspecialty training in liver and pancreatic surgery. He received his undergraduate degree from Harvard College and his medical degree from Washington University in St. Louis, completed his residency at University of California, San Francisco, and did a fellowship at Royal Postgraduate Med School in London. When Bernhoft became ill from environmental exposures, he retrained in environmental medicine and clinical metal toxicology in order to regain his health. He is now medical director of the Bernhoft Center for Advanced Medicine in Ojai, California, and president-elect of the American Academy of Environmental Medicine. Bernhoft speaks at national and international meetings on genomic medicine and environmental medicine. Visit his website: www.drbernhoft.com.

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ABSTRACT & COMMENTARY

Does Air Pollution Make Women Anxious? Teasing out the relationship between fine particulate exposure and mood REFERENCE

Power MC, Kioumourtzoglou MA, Hart JE, Okereke OI, Laden F, Weisskopf MG. The relation between past exposure to fine particulate air pollution and prevalent anxiety: observational cohort study. BMJ. 2015 Mar 24;350:h1111. DESIGN

This observational cohort study’s purpose was to determine whether higher past exposure to particulate air pollution can be associated with high symptoms of anxiety. PARTICIPANTS

The researchers selected 71,271 women enrolled in the Nurses’ Health Study (NHS) who lived in the contiguous United States and for whom valid data of particulate matter (PM) exposure were available during the time periods of interest. Ages ranged between 57 and 85 years (mean: 70 y). MEASURES

Particulate exposure Using home addresses, which were updated every 2 years as part of the NHS, the researchers used latitude and longitude data to estimate particulate air pollution exposure measured via levels of PM; this pollution was characterized by standard size categories (PM2.5 or PM10) during the 1-month, 3-month, 6-month, 1-year, and 15-year time periods prior to an assessment of the participants for anxiety symptoms. Distance of residence from major roads 2 years before anxiety assessment was also determined. Anxiety Anxiety levels were assessed using the Crown-Crisp index’s phobic anxiety subscale. KEY FINDINGS

Higher exposure to particulates in the PM2.5 range (<2.5 μm in diameter) was significantly associated with increased odds of high anxiety symptoms over multiple time periods. As an example, every per 10 µg/m3 increase in the prior 1-month average of PM2.5 increased odds of high-level anxiety by 12% (odds ratio [OR]:1.12; 95% confidence interval [CI]:1.06-1.19). This same increase in exposure to PM2.5 over the previous 12 months increased odds of high anxiety only slightly more, by 15% [OR:1.15, CI: 1.061.26]. Short-term exposure appeared more relevant than long-term exposure, with more recent exposures potentially more relevant than more distant exposures. Neither the larger particulate size PM10 (2.5 µm-10 µm in diameter) nor proximity of residence to major roads appeared to be associated with anxiety.

By Jacob Schor, ND, FABNO

PRACTICE IMPLICATIONS The potential link between particulate levels and anxiety levels is surprising. Until now, we have associated high levels of particulate matter mainly with cardiovascular disease (CVD) and respiratory illness; as Walter Crinnion, ND, notes in this issue of the Natural Medicine Journal, particulate matter is “associated with adverse effects in the respiratory, cardiovascular, and nervous systems, in addition to stimulating oxidative damage and inflammation.” The idea that PM pollutants might impact mood is relatively new. The majority of such papers have focused on depressive symptoms. In a 2012 article on premenopausal women in rural India, Bannerjee et al reported a strong correlation between depression and cooking with biomass pellets made of reprocessed organic material. The explanation offered to explain this association was the high PM levels in the participants’ homes, the result of this cooking method.1 Likewise, in a 2014 publication, Cho reported a significant association between air pollutant levels in Korea with the number of emergency room visits for depressive complaints.2 In a January 2015 review, Tzivian et al reported on 15 articles that related to the long-term effects of air pollution and ambient noise levels on cognitive and psychological function in adults. Their conclusion: “Both exposures were separately shown to be associated with one or several measures of global cognitive function, verbal and nonverbal learning and memory, activities of daily living, depressive symptoms, elevated anxiety, and nuisance.”3 Unfortunately no study examined both exposures at the same time, and it is often hard to separate the 2 factors.3 For example, an April 2015 study tells us that traffic wardens in Pakistan have above-average levels of depression, stress, public conflict, irritation, behavioral problems, speech interference, hypertension, loss of concentration, hearing impairment, headache, and CVD. The authors of this study blamed high noise levels for these cognitive effects, though they neglected to report PM exposure levels.4 One would suspect such exposure was high. A March 2014 study that sought an association between particulate matter levels and depression in Boston was unable to prove one5; this article was immediately criticized for its methodology.6

ABSTRACT & COMMENTARY

The smallest of the airborne particles (PM0.1 or smaller) are REFERENCES M, Siddique S, Dutta A, Mukherjee B, Ranjan Ray M. Cooking with biomass small enough to cross from lungs to blood and then across 1 Banerjee increases the risk of depression in pre-menopausal women in India. Soc Sci Med. 2012 Aug;75(3):565-572. the blood brain barrier to reach the brain. In addition, larger J, Choi YJ, Suh M, et al. Air pollution as a risk factor for depressive episode in particulates (PM2.5 and PM10) can carry small molecules 2 Cho patients with cardiovascular disease, diabetes mellitus, or asthma. J Affect Disord. 2014 Mar;157:45-51. such as solvent residue, which then traverses the alveoli and 3 Tzivian L, Winkler A, Dlugaj M, et al. Effect of long-term outdoor air pollution enters the bloodstream directly. This is probably why air and noise on cognitive and psychological functions in adults. Int J Hyg Environ Health. 2015;218(1):1-11. pollution is associated with stroke and depression in adults 4 Tabraiz S, Ahmad S, Shehzadi I, Asif MB. Study of physio-psychological effects on traffic wardens due to traffic noise pollution; exposure-effect relation. J Environ Health and why children exposed to pollution “show significant Sci Eng. 2015 Apr 16;13:30. systemic inflammation, immunodysregulation at systemic, 5 Wang Y, Eliot MN, Koutrakis P, et al. Ambient air pollution and depressive symptoms in older adults: results from the MOBILIZE Boston study. Environ Health intrathechal and brain levels, neuroinflammation and brain Perspect. 2014;122(6):553-558. oxidative stress, along with the main hallmarks of Alzheimer 6 Gao Y, Xu T, Sun W. Ambient air pollution and depressive symptoms in older adults. Environ Health Perspect. 2015;123(5):A114. and Parkinson’s diseases.”7 7 Calderón-Garcidueñas L, Calderón-Garcidueñas A, Torres-Jardón R, Avila-Ramírez J, This current report of a significant association with PM and anxiety should not come as a surprise. The only surprise is that we hadn’t considered this possibility until now. These results certainly have a clear clinical implication. We should consider the potential impact of air quality on any patient with anxiety symptoms.

Kulesza RJ, Angiulli AD. Air pollution and your brain: what do you need to know right now. Prim Health Care Res Dev. 2015;16(4):329-345. 8 Shah AS, Lee KK, McAllister DA, et al. Short term exposure to air pollution and stroke: systematic review and meta-analysis. BMJ. 2015 Mar 24;350:h1295.

ANOTHER SPECIAL ISSUE PUBLISHED BY

Potential improvement in anxiety symptoms might be achieved if patients simply use an air filter at home. Few medical interventions will come with a lower risk profile than this, a consideration often important for anxious patients. The potential side effects of using an air filter are all desirable, particularly reduced CVD risk and according to a March 2015 paper, reduced risk of stroke.8

ABSTRACT & COMMENTARY

Bisphenol A and Pregnant Women Study warns of fetal malformation in “poor metabolizers” of BPA REFERENCE

Guida M, Troisi J, Ciccone C, et al. Bisphenol A and congenital developmental defects in humans. Mutat Res. 2015 Apr; 774:33-39. Epub 2015 Mar 6. DESIGN

Case-control study PARTICIPANTS

One hundred fifty-one pregnant women were divided into 2 groups: the case group (n=101) consisted of women with established diagnosis of fetal malformation and the control group (n=50) consisted of women who visited the hospital during routine evaluations. STUDY INTERVENTION

Total, free, and conjugated bisphenol A (BPA) levels were measured in participants’ blood using gas chromatography–mass spectrometry with isotropic dilution. KEY FINDINGS

The average value of free BPA was nearly 3 times greater in the cases of chromosomal malformations and nearly 2 times greater in cases of central and peripheral nervous system nonchromosomal malformations compared to controls. Conjugated BPA levels, which were higher in the control group, support the hypothesis that a reduced ability to metabolize the chemical in the mother can lead to the occurrence of malformation in the fetus.

PRACTICE IMPLICATIONS Various studies point to BPA as an endocrine-disruptor that interferes with the programming of complex endocrine pathways during in utero and early childhood development.1-3 This is one of the first studies conducted in humans to explore the correlation between maternal blood BPA and fetal malformations. The most interesting observation from the study is that the control group with normally developed fetuses had higher levels of BPA conjugate compared to the case group of women with malformed fetuses. This finding reflects the ability of the control group to metabolize BPA to its inert form. The conjugated forms of BPA do not have endocrine-like activity and do not alter the biological processes of fetal development. Nonconjugated BPA binds to plasma proteins and interferes with the endocrine system, leading to fetal malformations. A study conducted by Matsumoto et al in 2002 on BPA pharmacokinetics demonstrated that the end result of BPA metabolism is eliminated via the kidneys as a water-soluble formation of BPA-glucuronide occurring via hepatic glucuronosyltransferase (GT).4 Another metabolite of BPA can occur, to a lesser degree, by sulfotransferase, resulting in the formation of BPA-sulfate. Hepatic GT activity is dependent on age and is much lower in fetuses and neonates.5 The major route of BPA metabolism in fetuses and neonates is via sulfation.6,7 This study clearly illustrates the environmental medicine concept of total body burden. The accumulation of toxicant load over time predisposes individuals to be more

By Jessica Tran, ND

susceptible to chronic illnesses and diseases. Reports of decreased fertility over the last decade may be attributed to long-term exposure to BPA, which has been linked to decreases in the percentage of oocytes that develop during meiosis II.8,9 The mechanism of action of BPA on oocytes remains unknown. From the study’s findings, the authors hypothesize the reduced ability to metabolize BPA may predispose a woman to pregnancies with fetal chromosomal abnormalities. These women can be classified as “poor metabolizers” who were more susceptible to the endocrine disruption of BPA. The results of the study also confirm the correlation between blood concentrations of total BPA in women with fetuses that had chromosomal abnormality compared to women with normally developed fetuses, as demonstrated by Yamada et al.10 It is imperative that clinicians educate patients on sources of BPA exposure to reduce or eliminate exposure for potential harm. Exposure to BPA is ubiquitous: the substance is found in plastics, linings of cans for food and beverages, thermal receipts, dental sealants, and self-adhesive labels, among several sources.11 A significant finding of this study highlights that those with normal biotransformation processes or ability to detoxify do not seem to exhibit the same deleterious effects of BPA as those who do are not able to clear exogenous compounds as well. Another focus in preconception care and infertility evaluation needs to be placed on identifying how well a woman can adequately clear toxicant exposures. Nutrients provided to patients prior to conception should focus on all aspects of biotransformation, especially on hepatic

ABSTRACT & COMMENTARY

GT activity to improve clearance of BPA to its nonactive forms and prevent harm to the developing fetus. Another note to emphasize is that BPA substitutes bisphenol S (BPS) and bisphenol-F (BPF) can also have the same endocrinedisrupting effects as BPA since they are as hormonally active.12 BPS and BPF can be found in the same sources as BPA—personal care products, paper products, and food. This study is a wake-up call to the role of BPA exposure on fetal development and human reproduction. Further exploration is warranted to determine its effects, if any, on male fertility and contribution to fetal malformation. REFERENCES 1 Suk WA, Murray K, Avakian MD. Environmental hazards to children’s health in the modern world. Mutat Res. 2003;544(2-3):235-242. 2 Wang MH, Baskin LS. Endocrine disruptors, genital development, and hypospadias. J Androl. 2008;29(5):499-505.

3 Unüvar T, Büyükgebiz A. Fetal and neonatal endocrine disruptors. J Clin Res Pediatr Endocrinol. 2012;4(2):51-60. 4 Matsumoto J, Yokota H, Yuasa A. Developmental increases in rat hepatic microsomal UDP-glucuronosyltransferase activities toward xenoestrogens and decreases during pregnancy. Environ Health Perspect. 2002;110(2):193-196. 5 Domoradzki JY, Thornton CM, Pottenger LH, et al. Age and dose dependency of the pharmacokinetics and metabolism of bisphenol A in neonatal Sprague-Dawley rats following oral administration. Toxicol Sci. 2004;77(2):230-242. 6 Chapin RE, Adams J, Boekelheide K, et al. NTP-CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A. Birth Defects Res B Dev Reprod Toxicol. 2008;83(3):157-395. 7 Suiko M, Sakakibara Y, Liu MD. Sulfation of environmental estrogen-like chemicals by human cystolic sulfotransferases. Biochem Biophys Res Commun. 2000;267(1):80-84. 8 Guzick DS, Swan S. The decline of infertility: apparent or real? Fertil Steril. 2006;86(3):524526; discussion 534. 9 Hamilton BE, Ventura SJ. Fertility and abortion rates in the United States, 1960-2002. Int J Androl. 2006;29(1):34-45. 10 Yamada H, Furuta I, Kato EH, et al. Maternal serum and amniotic fluid bisphenol A concentrations in the early second trimester. Reprod Toxicol. 2002;16(6):735-739. 11 Mikolajewska K, Stragierowicz J, Gromadzinsk J. Bisphenol A— Application, sources of exposure and potential risks in infants, children and pregnant women. Int J Occup Med Environ Health. 2015;28(2):209-241. 12 Rochester JR, Bolden AL. Bisphenol S and F: A systematic review and comparison of the hormonal activity of bisphenol A substitutes.Environ Health Perspect. 2015;123(7):643650.

ABSTRACT & COMMENTARY

Are Cosmetologists and Manicurists at Greater Risk for Pregnancy Complications?

By Anne Marie Fine, NMD

Study illuminates potential health risks for women in the nail and hair care industry REFERENCE

Quach T, Von Behren J, Goldberg D, Layefsky M, Reynolds P. Adverse birth outcomes and maternal complications in licensed cosmetologists and manicurists in California. Int Arch Occup Environ Health. 2014 Dec 14. [Epub ahead of print] DESIGN

This was a population-based retrospective study of cosmetologists and manicurists in California designed to examine adverse pregnancy outcomes as compared to both the general female population and to women working in other industries. A restricted analysis was also conducted for Vietnamese women who comprise a significant proportion of the nail and hair care workforce. PARTICIPANTS

The California licensing agency for cosmetologists and manicurists database, which included a total of 260,052 licensed cosmetologists and 159,430 licensed manicurists, was matched up to the birth registry files to identify births occurring between 1996 and 2009, a 14-year study period. The examined births were restricted to singletons and to women who were at least 18 years old at the age of birth. This resulted in 81,205 identified births among this group. For the 2 comparison groups, births during the same timeframe by women from the general population were frequency-matched at a 5-to-1 ratio by year of birth, resulting in 406,025 live births. The second comparison group consisted of women who had occupations on the birth records listed as teacher, realtor, salesperson, banker, office worker, and food service worker. This group totaled 53,056 live births. STUDY PARAMETERS ASSESSED

Outcome measures were birthweight, gestational age, selected birth defects, and infant death, as well as maternal preeclampsia, gestational and unspecified diabetes, premature rupture of membranes, placental abruption, plancenta previa, precipitous labor, and prolonged labor. PRIMARY OUTCOME MEASURES

Low birthweight was defined as less than 2,500 g (5.51 lb), preterm delivery defined as less than 37 weeks vs 37 weeks or more, and infant death defined as death during the first year of life. Babies below the 10th percentile of weight using sex-specific percentiles were identified as small for gestational age (SGA). Maternal outcomes included preeclampsia, gestational diabetes (data was available only for births between 2006 and 2009 since previous years did not specify “gestational diabetes” for those who

were identified as having diabetes), chronic diabetes, prolonged labor, precipitous labor, premature rupture of membranes, placental abruption, and placenta previa (data available for births between 1996 and 2005 only). KEY FINDINGS

Increased risk for adverse birth outcomes in cosmetologists and manicurists among all races was not observed. Cosmetologists had slightly reduced risk for low birthweight, SGA, and infant death compared to the general population. However, an increased risk of SGA in Vietnamese manicurists and cosmetologists was found when compared to other working women: odds ratio (OR):1.39; 95% confidence interval (CI):1.08-1.78 for manicurists and OR:1.40; 95% CI:1.08-1.83 for cosmetologists. These results were statistically significant. Some maternal complications were observed, most notably an increased risk for gestational diabetes (OR:1.28; 95% CI:1.101.50 for manicurists and OR:1.19; 95% CI:1.07-1.33 for cosmetologists) compared with the general population, which was further elevated when restricted to the Vietnamese workers (OR:1.59; 95% CI:1.2-2.11 for manicurists and OR:1.49; 95% CI:1.04-2.11 for cosmetologists). These results attained statistical significance. Unspecified diabetes also posed a statistically significant elevation in risk for manicurists (OR:1.36; 95% CI:1.08-1.71) compared with the general population. A less significant increased risk was observed in cosmetologists (OR:1.14; 95% CI:1.0-1.30) compared with the general population. These increases in risk were not statistically significant in the manicurists and cosmetologists when compared with other working women, although increases in risk were noted. There was also a statistically significant increase in risk of diabetes (unspecified) in the Vietnamese women breakout group of manicurists compared with the general population (OR:1.98; 95% CI:1.03-3.83) and also for gestational diabetes for the Vietnamese manicurists (OR:1.59; 95% CI:1.20-2.11) and cosmetologists (OR:49; 95% CI:1.04-2.11). Increased risk of premature rupture of membranes was statistically significant in manicurists but not cosmetologists as compared with other working women (OR:1.15; 95% CI:1.01-1.31) and as compared with the general population (OR:1.21; 95% CI:1.091.35). Increased risk of placentia previa was also statistically significant (OR:1.46; 95% CI:1.08-1.97 for manicurists and OR:1.22; 95% CI:1.02-1.46 for cosmetologists) when compared with the general population but was not statistically significant when compared with other working women.

(continued on page 24)

ABSTRACT & COMMENTARY

PRACTICE IMPLICATIONS As the authors of the present study note, manicurists and cosmetologists are exposed daily to an array of potentially hazardous chemicals associated with nearly every hair and nail care service they provide. These chemicals have received considerable attention in recent years because some of them are known or suspected carcinogens and endocrinedisruptors. Previous studies have demonstrated reproductive abnormalities in humans and animals exposed to these compounds. However, despite the growth of this industry and the numerous chemicals of concern found in salons, very few human health studies have been conducted in this area. An investigation of the nail worker industry was published in the New York Times on May 8, 2015.1 Titled “Perfect Nails, Poisoned Workers,” the article detailed the exploitation of these largely immigrant workers and the chronic health effects of near continual exposure to chemicals used in polishes, hardeners, glues, and solvents. The article serves as a flashpoint for awareness of this problem and even resulted in New York Governor Andrew Cuomo declaring emergency measures for this industry that addressed its egregious pay issues and mandated some basic salon worker safety measures. This action should also spur more research into the chemicals and chemical mixtures used in salons and their effects on the women who work there.

ylene, phthalates, and also BPA (with an OR reaching 2.74; 95% CI:1.44-5.23) after adjusting for age, gender, body mass index, and ethnicity. Salons are rife with endocrine- disruptors, including BPA and phthalates. As so many of these chemicals are endocrine-disruptors, the increased risk for diabetes is not surprising. It would have been interesting to look for other endocrine disruptions, such as thyroid disease, hormonal perturbations, and congenital abnormalities like hypospadias, since endocrine-disruptors often cause these conditions. Numerous studies have been focused on the association between endocrine-disrupting chemicals and hypospadias. In a recent study carried out in France, fetal exposure to endocrine-disruptors during the window of genital development was more frequent in the case of hypospadias (OR:3.13; 95% CI:2.11-4.65).3 Furthermore, hairdressers and beauticians were identified, along with cleaners and lab workers, as professionals with the most exposure to these substances, and these women were more frequently the mothers of hypospadiac boys. In addition, according to the authors of this study, “the types of substances having an impact on the phenotype were heterogeneous, but detergents, pesticides, and cosmetics accounted for 75 percent of the cases.”3 The authors elucidated some of the endocrine-disrupting chemicals linked to the professions involved in the study: BPA, phthalates, polychlorinated compounds, alkylphenolic compounds, and organic solvents.

While this study found no adverse effects on the children, save the low SGA in Vietnamese women, there were several adverse effects in the women themselves. Risk for gestational diabetes, premature rupture of membranes, and placenta The study being reviewed did not examine miscarriage rates previa were all significantly higher in the cosmetologists and among manicurists and cosmetologists. However, previous studies have found some evidence of both increased rates manicurists. of miscarriage and time-to-pregnancy in hairdressers.4 In 1 A higher risk of diabetes in those exposed to endocrine- study, female hairdressers were found to have an increased disruptors is not new information. In 2004, the National risk of infertility (OR:1.30; 95% CI:1.08-1.55) and an Health and Nutritional Examination Survey (NHANES) increased risk of spontaneous abortion (OR:1.31; 95% found a similar association.2 The NHANES analyses showed CI:1.07-1.60).5 Others studies failed to find such an associathat most participants have detectable blood and/or urine tion that reached statistical significance.4 levels of several chemicals, in particular bisphenol A (BPA). Diabetes was strongly associated with exposure to polychlo- Volatile solvents such as formaldehyde, methacrylates, rinated biphenyl, dioxins, dichlorodiphenyldichloroeth- acetone, xylene, and toluene, as well as parabens and 24 ©2015 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, SEPTEMBER 2015 SUPPLEMENT—VOL. 7, NO. 91 (SUPPL)

ABSTRACT & COMMENTARY

hthalates, are just some of the chemicals found in these p salons. Nail products typically contain the trifecta of toxicants: toluene, formaldehyde, and phthalates.6 Some nail polish manufacturers have reformulated their nail polish to be free of the toxic 3. Disturbingly, however, California regulators in 2012 tested 25 randomly chosen nail polishes from 6 distributors that sell to many of the 48,000 salons in California and found the toxic trio in several of the samples chosen. According to the report, 10 of the 12 polishes that claimed to be free of toluene actually contained the substance. Five of 7 products that claimed to be free of all 3 chemicals were found to contain 1 or more of the chemicals at elevated levels.7 It cannot be inferred if the polish labels were deliberately misleading or if a vendor in the supply chain had misrepresented the chemical makeup of their ingredients unbeknownst to the formulator of the final, finished product.

Phthalates have been found to be associated with earlier breast and pubic hair development in girls exposed in the peripubertal timeframe as well as genital variations in infant boys exposed prenatally and neurobehavioral issues in schoolage boys.11-13 These findings are concerning because there are often biological responses to the same doses of chemicals found in everyday exposure to common household and personal care products.

In a study of occupational urinary phthalate metabolites found across 8 different industries, levels of phthalates in salon workers were found to be twice as high relative to the general population.9 In another study, indoor air was tested for phthalates in homes, offices, laboratories, schools, hair and nail salons, and public places. The highest concentration was found in the salons, at 2,600 ng/m3; the second highest concentration of phthalates was found in the homes, at 732 ng/m3.10 Inhalation is an important exposure route for humans, so these levels bear further study for their health effects. Also, consideration of the contributors to home indoor air that contains high levels of phthalates is warranted when evaluating patients for toxic exposures.

burden. We should elicit information about the chemicals and chemical processes that are suspected of containing endocrine-disrupting chemicals that have been shown to be associated with poorer pregnancy outcomes and maternal health. Because females of reproductive age make up the majority of this population, awareness of toxicants in their environment can and should be a part of their treatment plan, particularly if these women wish to conceive. More research is needed to understand possible occupational reproductive and other health risks for cosmetologists due to the sheer number of chemical products that they are exposed to on a daily basis. Finally, personal care product safety as a whole needs to be more extensively studied.

Solvent exposure poses its own risks. In a recent study that examined pregnant women, including hairdressers, and their occupational exposure to solvents, significant associations were found between major congenital malformations and maternal exposure to solvents—OR:2.48; 95% CI:1.4-4.4 for regular exposure vs no exposure based on self-reporting, which jumped to the occupationally derived solvent matrix result (OR:3.48; 95% CI :1.4-8.4 for highest level of expoAs with other chemicals that have been found to be detrimental sure vs no exposure). A significant dose-response trend was to human health, the “cure” is sometimes illusory and diffiobserved with both assessment levels. The congenital malforcult to rely upon. In the case of BPA, BPS and BPF and other mations were mainly oral clefts, urinary malformations, and analogs used as substitutions have been found to be similarly male genital malformations.14 hormonally active as BPA and also have endocrine-disrupting effects.8 It stands to reason that chemical substitutions for From a clinical perspective, it behooves us to evaluate our problematic chemicals need to be thoroughly vetted as well. manicurist and cosmetologist patients for toxicant body

ABSTRACT & COMMENTARY

REFERENCES 1 Maslin Nir S. Perfect nails, poisoned workers. New York Times. May 8, 2015. Available at:http://www.nytimes.com/2015/05/11/nyregion/nail-salon-workers-in-nyc-facehazardous-chemicals.html. Accessed August 3, 2015. 2 Chevalier N, Fenichel P. Endocrine disruptors: New players in the pathophysiology of type 2 diabetes? Diabetes Metab. 2015;41(2):107-115. 3 Kalfa N, Paris F, Philbert P et al. Is hypospadias associated with prenatal exposure to endocrine disruptors? A French collaborative controlled study of a cohort of 300 consecutive children without genetic defect. Eur Urol. 2015 May 23; pii:s03022838(15):0409-1. 4 Axmon A, Rylander L, Lillienberg L, Albin M, Hagmar L. Fertility among female hairdressers. Scand J Work Environ Health. 2006;32(1):51-60. 5 Baste V, Moen BE, Riise T, Hollund BE, Oyen N. Infertility and spontaneous abortion among female hairdressers: the Hordaland Health Study. J Occup Environ Med. 2008;50(12):1371-1377. 6 Quach T, Doan-Billing P, Layefsky M et al. Cancer incidence in female cosmetologists and manicurists in California, 1988-2005. Am J Epidemiol. 2010;172(6):691-699 7 Environmental Working Group. Calif. Regulators: “Non-Toxic” Nail Polishes Anything But. April 10, 2012. Available at:http://www.ewg.org/news/news-releases/2012/04/10/ calif-regulators-%E2%80%9Cnon-toxic%E2%80%9D-nail-polishes-anything. Accessed August 3, 2015. 8 Rochester JR, Bolden AL. Bisphenol S and F: a systemic review and comparison of the hormonal activity of bisphenol A substitutes.Environ Health Perspect. 2015;123(7):643650.

9 Hines CJ, Nilsen Hopf NB, Deddens JA, et al. Urinary phthalate metabolite concentrations among workers in selected industries; a pilot biomonitoring study. Ann Occup Hyg. 2009;53(1):1-17. 10 Tran TM, Kannan K. Occurrence of phthalate diesters in particulate and vapor phases in indoor air and implications for human exposure in Albany, New York, USA. Arch Environ Contam Toxicol. 2015;68(3):489-499. 11 Wolff MS, Teitelbaum SL, Pinney SM, et al. Investigation of relationships between urinary biomarkers of phytoestrogens, phthalates, and phenols, and pubertal stages in girls. Environ Health Perspect. 2010;118(7):1039-1046. 12 Kobrosly RW, Evans S, Miodovnik A, et al. Prenatal phthalate exposures and neurobehavioral development scores in boys and girls at 6-10 years of age. Environ Health Perspect. 2014;122(5):521-528. 13 Ormond G, Nieuwenhuijsen MJ, Nelson P, et al. Endocrine disruptors in the workplace, hairspray, folate supplementation, and risk of hypospadias: case control study. Environ Health Perspect. 2009;117(2):303-307. 14 Garlantezec R, Monfort C, Rouget F, Cordier S. Maternal occupational exposure to solvents and congenital malformations: a prospective study in the general population. Occup Environ Med. 2009;66(7):456-463.

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ABSTRACT & COMMENTARY

Low-dose Chemical Mixtures as Carcinogens The effects of multiple toxins on the human body, and what it means for the future of healthcare REFERENCE

Goodson WH 3rd, Lowe L, Carpenter DO, et al. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis. 2015;36 Suppl 1:S254-S296. DESIGN

Eleven teams of international toxicologists and biologists reviewed relevant data on ubiquitous chemicals and their possible influence on carcinogenesis based on the “hallmarks of cancer.”1 Each team was to determine “prototypical” chemicals that are involved in the given hallmark. The 11 teams were assigned to these categories: angiogenesis, dysregulated metabolism, evasion of antigrowth signaling, genetic instability, immune system evasion, replicative immortality, resistance to cell death, sustained proliferative signaling, tissue invasion and metastasis, tumor microenvironment, and tumor-promoting inflammation. Each team was tasked with determining chemical compounds that affect the given pathway and are (1) ubiquitous in the environment, (2) not known carcinogens, (3) not “lifestyle”-related (eg, fried foods, smoking), and (4) “selectively disruptive” to the assigned hallmark of cancer. The teams were further tasked to determine the level of exposure necessary to elicit effects on the given pathway and whether a linear or nonlinear relationship to the given chemical’s action exists. KEY FINDINGS

In total, 85 chemicals were deemed prototypical disruptors of 1 or more hallmarks of cancer. Fifty out of the 85 chemicals (59%) exerted low-dose effects (“at levels that are deemed relevant given the background levels of exposure that exist in the environment”). Fifteen of these 50 had a nonlinear dose-response pattern. Thirteen of the 85 prototypical agents (15%) had a dose-response threshold. Twenty-two of the 85 agents (26%) lacked sufficient information to define any doseresponse relationship.

By Tina Kaczor, ND, FABNO

PRACTICE IMPLICATIONS There is an axiom in toxicology that “the dose makes the poison.” The implication is that a chemical is innocuous until some threshold dose is reached, at which point it can have toxic effects. When considering carcinogens, this is useful for single agents that have proven thresholds (eg, arsenic, asbestos). This type of direct dose-related effect allows for classification of chemicals by carcinogenic potential.2 This singular dosedetermined carcinogenic potential is relevant for occupational exposures, contaminated land/water, and other high-dose exposure scenarios. However, what if there is synergistic carcinogenic potential resulting from hundreds of low doses of chemicals that are going unnoticed? What if dozens of chemicals work together on multiple molecular pathways to culminate in carcinogenesis? These are very practical questions given that such exposures are the reality of our everyday existence. They are also of great relevance because cancer is a close second only to heart disease as the most common cause of death in the United States.3 Given these considerations, such questions should take on immediacy in toxicology research. However, the dominant paradigm is still based on the old axiom “the dose makes the poison.” What if there is synergistic carcinogenic potential resulting from hundreds of low doses of chemicals that are going unnoticed? What if dozens of chemicals work together on multiple molecular pathways to culminate in carcinogenesis? The government-funded Agency for Toxic Substances and Disease Registry (ATSDR) has taken a stance on the role of ubiquitous chemicals and cancer causation in its publication Chemicals, Cancer and You.4 In it, the ATSDR notes, “More than 100,000 chemicals are used by Americans, and about 1,000 new chemicals are introduced each year. These chemicals are found in everyday items, such as foods, personal products, packaging, prescription drugs, and household and lawn care products.” Later in the same document is a disconcerting disconnect between these facts and ATSDR’s conclusion that “[t]hese everyday exposures are usually too small to cause health problems.” This, of course, is the old axiom of toxicology at work. ATSDR is an official agency whose purpose is to “increase knowledge about toxic substances, reduce the health effects of toxic exposures, and protect the public health.” Pervasive throughout its official publications is the notion that carcinogens are singular substances deemed to cause cancer at some

ABSTRACT & COMMENTARY

threshold dose.5 The conclusion that combinations of low levels of chemicals are harmless is based on a lack of research, not research suggesting safety of chemical mixtures. As the adage goes, “the absence of evidence is not evidence of absence.”

interest in the disease in a manner that ultimately results in societal changes that reduce the public exposure to disruptive environmental agents that can act in concert with one another to instigate cancer.”6 The gathering was sponsored by the National Institute of Environmental Health Science, The paper reviewed here posits a means to systematically a division of the National Institutes of Health. study the effects of multiple chemicals that more realistically mimics current environmental exposures. It is, essentially, The consortium continues its ongoing work to lay the founa paradigm shift. Using the “hallmarks of cancer” as the dation for this emerging concept, namely the “low-dose carciframework to understand the various attributes of chemicals nogenesis hypothesis.” Perhaps the authors best summarize in relation to cancerous processes, research can investigate the utility of the paper reviewed here: common environmental chemicals and discern whether a The chemicals that were selected for this review were not chemical affects a given pathway(s) and at what dose. This deemed to be the most important, and they were not selected leads to a better understanding of synergistic effects on carcito somehow imply (based on current information) that they nogenic processes, even by chemicals considered noncarare endangering us. Rather, we simply wanted to illustrate that cinogens as single agents. many non-carcinogenic chemicals (that are ubiquitous in the Of the 85 chemicals that were found to affect key pathways environment) have also been shown to exert effects at low doses, related to carcinogenesis, only 15% (13/85) were found to which are highly relevant to the process of carcinogenesis. have a dose-response threshold, the classic dose threshold model of toxicity. Low-dose effects were predominant in EDITOR’S NOTE 59% (50/85) of the compounds. The authors concluded, The article reviewed here is not a clinical trial; it is a paper “Our analysis suggests that the cumulative effects of indi- written by a consortium of scientists who looked at the vidual (non-carcinogenic) chemicals acting on different path- evidence for carcinogenic potential of commonly used chemiways, and a variety of related systems, organs, tissues and cells cals. We normally review only studies using human data in could plausibly conspire to produce carcinogenic synergies.” the Abstracts & Commentary section, but since this is such important work and represents a paradigm shift, the editorial Some of the chemicals found to disrupt key pathways that team made an exception. contribute to the various hallmarks include bisphenol A (BPA), phthalates, nickel, cadmium, diazinon, and malaREFERENCES thion. Avoidance of chemical ingestion—whether from 1 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5): 646-674. water, air, or food—is clearly the wisest option. Unfortu2 World Health Organization. Agents classified by the IARC monographs, volumes 1-113. nately, it is not a feasible option given the ubiquity of chemiAvailable at:http://monographs.iarc.fr/ENG/Classification/. Accessed August 28, 2015. cals in our environment. 3 US Centers for Disease Control and Prevention. Faststats: Leading causes of death. The paper under review was not a small undertaking. It is a result of an ambitious project that began with a consortium of scientists from many disciplines that first met in Halifax, Nova Scotia, in 2013. The meeting was hosted by the organization Getting to Know Cancer. The mission statement for Getting to Know Cancer is “To share holistic, scientific knowledge about cancer with key stakeholders who have an

Available at: http://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm. Updated August 21, 2015. Accessed August 28, 2015. 4 Agency for Toxic Substances and Disease Registry, Division of Health Assessment and Consultation. Chemicals, Cancer, and You. Available at: http://www.atsdr.cdc.gov/ emes/public/docs/Chemicals,%20Cancer,%20and%20You%20FS.pdf. Accessed August 28, 2015. 5 US Department of Health and Human Services, National Toxicology Program. Definition of carcinogenicity results. Available at: http://ntp.niehs.nih.gov/results/pubs/longterm/ defs/index.html. Accessed August 28, 2015. 6 Getting to Know Cancer. Mission. Available at: http://www.gettingtoknowcancer.org/ visionmission.php. Accessed August 28, 2015.

ABSTRACT & COMMENTARY

Air Pollution Aggravates Diabetes Study links particulate matter levels and diabetes-related hospitalizations REFERENCE

Solimini AG, D’Addario M, Villari P. Ecological correlation between diabetes hospitalizations and fine particulate matter in Italian provinces. BMC Public Health. 2015;15(1):708. DESIGN

Cross-sectional data were aggregated from Italian institutional and regional databases from 2008 through 2010 to determine correlations between hospital discharges with diabetes and fine particulate matter (PM2.5) levels, adjusting for common risk factors and socioeconomic factors. DATA

The data cover 48 Italian provinces, with a population of more than 34 million residents (60% of the total Italian population). The particulate matter up to 2.5 micrometers in size (PM2.5) average levels between 2008 and 2010 in the Italian provinces ranged between 11 μg/m3 to 32 μg/ m3 with a mean of 20.1 μg/m3. Diabetes hospital discharge in patients older than 45 years ranged for women between 4.6 to 66.9 per 10,000 with a mean of 16.2; the range for men was between 8.4 and 83.8 per 10,000 with a mean of 23.4.

By Julianne Forbes, ND, and Jacob Schor, ND, FABNO

PRACTICE IMPLICATIONS This paper suggests that controlling exposure to air pollution may reduce incidence of diabetes and complications (in particular, hospitalizations) for diabetics. This is a connection that few practitioners think of when working with this patient population. While we are well aware that what and how much we eat impacts weight, metabolic syndrome, and diabetes, these 2 factors do not take into consideration how well we process calories. Increasing evidence shows that overexposure to environmental toxins from all sources can negatively affect human metabolic pathways. At least 5 cohort studies have sought an association between air pollution and type 2 diabetes. Krämer reported in 2010 that traffic-related air pollution was associated with incident type-2 diabetes among elderly women in the industrialized Ruhr region of Germany.1 A 2013 study that examined a cohort of more than 60,000 people in Ontario, Canada, reported an 11% increase in diabetes incidence per 10 μg/m3 increase in PM2.5.2

ANOTHER SPECIAL ISSUE PUBLISHED BY

PARTICULATE MEASURES

Annual levels of PM2.5 of Italian cities were obtained in hourly measurements from monitoring stations belonging to regional networks. The time period and the monitoring stations were chosen to match the hospital discharge data at the provincial level. KEY FINDINGS

Diabetes hospitalizations increased with increased annual PM2.5 concentrations, with a rise of 3.5% (1.3%-5.6%) for men and of 4.0% (1.5%-6.4%) for women per μg/m3 of PM2.5 increase.

ABSTRACT & COMMENTARY

This study contrasts a report published in 2012 that, while finding a 25% increase in diabetes with interquartile increases in nitrogen dioxide (NO2) in a cohort of black women living in Los Angeles, did not find an association between diabetes and fine particulates.3 Two other US prospective cohorts also failed to find associations with diabetes and PM2.5 or PM10, yet they did find an association with “distance to road,” a stand-in marker for traffic-related pollution.4 In Denmark, Andersen et al found a borderline statistical association between confirmed cases of diabetes and NO2 levels.5 Pearson et al in 2010 reported a 1% increase in diabetes with an increase by 10 μg/m3 of PM2.5.6

cohort was exposed to lower PM2.5 concentrations—2.5 μg/m3 to 17.7 μg/m3 (median=11 μg/m3)—compared to the people in this Italian study, whose exposure was 11 μg/m3 to 32 μg/m3 with a higher median equal to 8.68 μg/m3. Mechanisms exist to explain a possible association, in particular that the air pollutants increase systemic oxidative stress and trigger inflammatory changes that lead to insulin resistance.7,8 In animals, exposures to persistent organic pollutants are consistently associated with insulin resistance and type 2 diabetes.9 In addition, a review outlined how toxins can provoke insulin resistance through debilitated thyroid function and mitochondrial injury.10

This current Italian study suggests a greater risk increase than Pearson, a 35% increase for men and a 40% increase for Several studies now suggest that indoor air filtration systems, women per 10 μg/m3 PM2.5. We should note that Pearson’s by reducing PM2.5 levels, also decrease markers of cardiovascular disease risk.11,12 Using the same manner of intervention, cleaning indoor air via filtration may potentially prove useful ANOTHER SPECIAL ISSUE in treating insulin resistance, lowering incident diabetes, and reducing risk of diabetic complications and hospitalizations. PUBLISHED BY REFERENCES 1 Krämer U, Herder C, Sugiri D, et al. Traffic-related air pollution and incident type 2 diabetes: results from the SALIA cohort study. Environ Health Perspect. 2010;118(9):1273-1279. 2 Chen H, Burnett RT, Kwong JC, et al. Risk of incident diabetes in relation to longterm exposure to fine particulate matter in Ontario, Canada. Environ Health Perspect. 2013;121(7):804-810. 3 Coogan PF, White LF, Jerrett M, et al. Air pollution and incidence of hypertension and diabetes mellitus in black women living in Los Angeles. Circulation. 2012;125(6): 767-772. 4 Puett RC, Hart JE, Schwartz J, Hu FB, Liese AD, Laden F. Are particulate matter exposures associated with risk of type 2 diabetes? Environ Health Perspect. 2011;119(3):384389. 5 Andersen ZJ, Raaschou-Nielsen O, Ketzel M, et al. Diabetes incidence and long-term exposure to air pollution: a cohort study. Diabetes Care. 2012;35(1):92-98. 6 Pearson JF, Bachireddy C, Shyamprasad S, Goldfine AB, Brownstein JS. Association between fine particulate matter and diabetes prevalence in the U.S. Diabetes Care. 2010;33(10):2196-2201. 7 Xu X, Liu C, Xu Z, et al. Long-term exposure to ambient fine particulate pollution induces insulin resistance and mitochondrial alteration in adipose tissue. Toxicol Sci. 2011;124(1):88-98. 8 Sun Q, Yue P, Deiuliis JA, et al. Ambient air pollution exaggerates adipose inflammation and insulin resistance in a mouse model of diet-induced obesity. Circulation. 2009;119(4):538-546. 9 Rajagopalan S, Brook RD. Air pollution and type 2 diabetes: mechanistic insights. Diabetes. 2012;61(12):3037-3045. 10 Hyman M. Systems biology, toxins, obesity, and functional medicine. Altern Ther Health Med. 2007;13(2):S134-S139. 11 Chen R, Zhao A, Chen H, et al. Cardiopulmonary benefits of reducing indoor particles of outdoor origin: a randomized, double-blind crossover trial of air purifiers. J Am Coll Cardiol. 2015;65(21):2279-2287. 12 Weichenthal S, Mallach G, Kulka R, et al. A randomized double-blind crossover study of indoor air filtration and acute changes in cardiorespiratory health in a First Nations community. Indoor Air. 2013;23(3):175-184.