Changing Evolving Directions Priorities in Environmental

Health

Michael GochfeldProfessor Emeritus Rutgers University

Environmental & Occupational Health Sciences InstituteMARCOEM 2018

Environmental Health Conference: 1990

• Moderator to Dr. Bernard Goldstein, what do you expect will be the pressing environmental problems of the next millennium.

• BDG Answer: I can tell you confidently that it will Include problems that none of us are thinking of today.

• Think genomics, nanoparticles, cell phone exposure, Fracking, PFOA pharmaceuticals and hormones

DISCLAIMER

• I have been accused of making political statements in some lectures.• So let me beclear upfront that environmental health and

environmental health research are intrinsically interwoven with policies and politics.

• My background embraces ecology and evolution

• I accept the label “environmentalist” which has been used as a term of “opprobrium”

• i.e.”to link someone to a shameful act”

1970 Environmental Problems

• Air pollution• Water pollution• Lead poisoning• Pesticides

Traditions that re-emerge from time to time

• Lead---now in drinking water• Mercury---now in gymnasium floors• Pesticide exposures in children on farms around the World

Dose-response curve (monotonic)• Based on the

cumulative response curve on the right, Approximately what is the NOAEL .

• 0.5 1 1;5 2

• Threshold • 0.5 1 1.5 2

• ED50 • 1. 1.5 2

And yet

• Only a few hundred chemicals have been tested “Extensively” in animals.

• And we can’t test most substances experimentally in humans.

• We rely on extrapolations, structure-activity relationships and expert opinions (guesses)

International Effort

• Dr. Goldstein and HIS MENTOR Norton Nelson, were among the founders of the

• SGOMSEC• Scientific Group on Methodologies for the Safety Evaluation of

Chemicals. • During its 20 years of existence it did examine evolving

methodologies in keeping with its name.• Animal models• Non-animal models• Neurobehavioral techniques

Slow progress in establishing causation and criteria values • Epidemiologic studies:expensive, • plagued by small sample sizes, • uncertain exposure assessments. • And corporate resistance or corporate-conducted

• Through the 1960’s and 1970’s and even into the 1990ssas evidence accumulated. • The tobacco industry pro-claimed, “there is no proof”, • Neither was there “any doubt • What do we mean by “proof” in environmental epidemiology• Smoking caused lung cancer and heart disease (never admitted)• Smoldering battle over second-hand smoke

Not just tobacco

• Lead warsDavid Michaels: “Doubt is their Product”Markowitz & Rosner “The Lead Wars”

• Asbestos • Efforts today to re-legitimatize asbestos use

Barry Castleman “Asbestos”Devra Davis: “The Secret History of the War on Cancer”

• Non-ionizing radiation• Do cell phones cause cancer? If so in who?• Devra Davis: “Wired: The Truth About Mobile Phone and Wireless Radiation”

• Wherever there is a regulation on the horizon, there is an opposition• Ascendancy of the anti-regulation movement

And an anti-science movement as well

The “Honesty Act” is Dishonest

• It uses “transparency” • Dr. Goldstein called attention to an act which would block agencies

(EPA particularly) from using data UNLESS all data were available for scrutiny and re-analysis

• It would allow corporate-produced data to be used even after re-adactions.

• Recent Appropriations bill included a rider that would prevent US funds to support IARC Monograph work

• Fortunately the rider was stripped by Congress

This challenge will have to be met with other tools besides or in addition to • Regulations and Standards

• Protection of SCIENCE and EVIDENCE• Education of the citizenry• Marketplace factors• International pressures• Safety culture

• OSHA faced this under the rubric of “harmonization”

Disinformation has been effective in raising doubt

• Try to create impression of “honest” disagreement in face of consensus• See David Michaels: DOUBT IS THEIR PRODUCT

• Harass scientists: Attack on Herb Needleman• Create Confusion: Will the real Joel Schwartz please stand• Pay for publications (scientists for hire)• Buy Journals so you can show COURTS peer-reviewed articles

Joel Schwartz and Lead

Will the real Joel Schwartz please stand

Asbestos

After more than a decade this conspiracy was uncovered

• International Journal of Occupational and Environmental Health• Purchased by Taylor & Francis• New publisher fires old editor• Hired Dennis Paustenbach leading “corporate” risk assessor as editor

• International Journal of Occupational and Environmental Health is not accepting any new submissions.

“There is no proof that smoking causes cancer” • But neither is there any doubt

• Would the Surgeon General’sReport (1964) get published today

In Washington’s anti-evidenceculture

1970’s New Jersey sets the pace for the US• Oldest industrialized state• High % of workforce in chemical/pharmaceutical/petrochemicals• More toxic chemical waste sites• Disproportionate frequency of waste disposal• 1977 The NJ Spill Compensation Fund Claims Program • 1980’s CERCLA Comprehensive Environmental Response, Compensation, and Liability Act

“Superfund”• NJ Worker and Community Right-to-Know

• OSHA Hazard Communication Standard• Less restrictive• Pre-empted NJ

•

1978 Star Ledger Poll

• #1 issue was “Environment” (particularly toxic waste)

• Ahead of crime, economy, employment

• 1980 Rutgers Medical School hires • Dr.Goldstein to build environmental medicine

Genetics and susceptibility

• 1970 Susceptibility was barely recognized as an issue in toxicology• 1980 Recognition that liver toxicity could be predictable vs non-predictable• 1990 Risk assessments assumed that humans were 10x more “sensitive” to

chemicals than animals, and • Moreover that “sensitive” humans were 10x more sensitive than average. • FOR EXAMPLE EPA’s DEFINITION OF REFERENCE CONCENTRATION• “An estimate (with uncertainty spanning perhaps an order of magnitude) of

a daily inhalation exposure to the human population (including sensitivesubgroups) that is likely to be without appreciable risk of deleterious effects during a lifetime”

Predictable vs idiosyncratic Hypersensitivity due to HLA-B*57:01 allelle (Human leukocyte antigen)

INTR

INS

IC T

OXI

CIT

Y

Low relevance Host susceptibility high relevance

Aflatoxinb1

penicillin

LOW

HIGH

Ecologic & Evolution Considerations of

• 1946 Microbial resistance to chemotherapeutic drugs. Brit Med Bull

• 1961 On the drug-resistance of enteric bacteria. 6. Spontaneous and artificial elimination of transmissible drug-resistance factors. Japan J ExperMed.

• Strains of resistant and susceptible inbred rodents• Resistance genetics (rare genetic variants survive)

• Antibiotics select for bacterial resistance (2nd gen penicillin resist beta-lactamase)• Insecticides select for insect resistance• Cancer drugs select for cancer resistance

1990s GENOMICS (2 themes)

• 1990 Human Genome Project officially begins (Oct 1990)• 1992 First papers on BRCA genes • 1995 Human DNA sequencing begins

• Map of Human chromosome 7 is completed• 1999 Rapid sequencing technology introduced

• 1995 Ethical, Legal and Social Implications Working Group• 1996 New Jersey passes law protecting against genetic discrimination• 1997 Committee addressed potential genetic discrimination at work

2000

• 2000 President Clinton Exec Order prevent genetic discrimination in workplace

• 2002 Familial prostate gene identified on chromosome 1• 2003 Human genome sequence completed

• Now what?• How can this info be used to predict, prevent, and treat• October 14, 2003: The U.S. Senate passes the Genetic Information

Nondiscrimination Act of 2003 by a vote of 95-0,• The bill prevents health insurers and employers from using genetic

information to determine eligibility, set premiums, or hire and fire people.

2005

• 2005: Catalog of human genetic variation accelerates the search for disease genes (asthma, diabetes, cancer and heart disease).

• 2007: Genetic risk factors for diabetes identified• NIH funding for technology to sequence individual genomes• Start of the Human Microbiome Project• May 21, 2008: President Bush signs Genetic Information

Nondiscrimination Act (GINA).• 2009 Functional genomics (or how sequences work) involving 3D

visualization of gene regions

DNA Adducts

• Chemical carcinogens (PAH), • Adducts on DNA in cigarette smokers• Rapid quest for additional examples• Adducts as biomarkers of exposure and risk

• Aflatoxin adducts in China• PAH adducts and charboiled meat in California

• DNA adducts and lung cancer risk: a prospective study (Italy 2005)• Risk of lung cancer higher with DETECTABLE adducts OR=1.86 [0.88-

3.93] • Association stronger in never smokers OR=4.04 [1.06-15.4]

1983 100

1975 11996 593

Genomics in pubmed

• 1987 “Genomics” 55 papers >20,000/year today• 1947 gene-environment 1 paper and >10,000/year today

• Mostly related to agriculture• 2018

• MOST RECENT Rs4938723 Polymorphism Is Associated with Susceptibility to Hepatocellular Carcinoma Risk and Is a Protective Factor in Leukemia, Colorectal, and Esophageal Cancer [Gene: pri-miR-34b/c

• Drug pharmacomicrobiomics and toxicomicrobiomics: from scattered reports to systematic studies of drug-microbiome interactions.

• Each NIH disease institute now incorporates genomics

Knockout Mice 1991=1

2016=10K

Phase 1 Metabolism

• Collectively referred to as Mixed Function Oxidases• Cytochrome P-450s and oxidation, hydroxylation reactions• Aryl hydrocarbon hydroxylase induction by aromatics

• Activates benzo[a]pyrene • Now identified as Cyp1A1• High inducibility of AHH when xenobioticBinds to Ah receptor. High inducibility is a risk factor for lung cancer

Debrisoquine metabolism • The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6

gene, AJHG (1989)• EM extensive metabolizer of debrisoquine• PM poor metabolizer• Europeans (5-10% are PM)• CYP2D6 gene sequenced 1988• About ¼ of drugs metabolized by hydroxylation, demethylation, dealkylation, • poor metabolizer – little or no CYP2D6 function

• NOW CAN GENOTYPE AND IDENTIFY • intermediate metabolizers – metabolize drugs at a rate somewhere between the poor and extensive

metabolizers• ultrarapid metabolizer – multiple copies of the CYP2D6 gene are expressed, so greater-than-normal CYP2D6

function occurs

19911

Genetic variation and single nucleotide polymorphisms (SNPs)• Epidemiologic studies linking SNPs to risk• glutathione S-transferase(GSTM1; GSTT1; GSTP1); • N-acetyltransferase (NAT1; NAT2); • sulfotransferase 1A1 (SULT1A1); • catechol-O-methyltransferase (COMT); • NAD(P)H:quinone oxidoreductase (NQO1);

GENE EXPRESSION STUDIESSome studied enzyme activity

Others studied the mass of enzyme protein

2000600

2015 11K

Phase 2: GLUTATHIONE-S-TRANSFERASE

• GSTs can constitute up to 10% of cytosolic protein• GSTs catalyse the conjugation of GSH—to electrophilic centers

xenobiotics/metabolites• Makes large non-polar compounds more water-soluble.• detoxifies endogenous compounds such as peroxidised lipids and

enables the elimination of xenobiotics in diet.• Different genetic variants (single nucleotide polymorphisms)

influence the enzyme kinetics

Glutathione S-transferase polymorphisms: cancer incidence and therapy.

• McIlwain 2006 Oncogene. 25(11):1639-48.• The super family of glutathione S-transferases (GSTs) is composed of

multiple isozymes • significant functional variation. • SNPs could be used to recognize susceptibility, prognosis and

treatment.

Microbiomics and Toxicology

• Drug pharmacomicrobiomics and toxicomicrobiomics: from scattered reports to systematic studies of drug-microbiome interactions

• Microbiome affects metabolism and absorption of• Cardiovascular drugs• Chemotherapeutics, • Antibiotics

• The gut microbiota has been the most extensively studied• Big Data: Computational resources, moving the field from cataloguing to

predicting interactions,• pharmacomicrobiomic testing is expected for drug design and screening• It’s hard for me to appreciate how arrays of DNA sequences relate to living and

breeding microorganisms

2017 880

Environmental Health Consequences of Energy Alternatives• All energy generation has a footprint on the landscape• Natural gas is considered a “clean” fuel• Hydrofracturing of rock (“fracking”) produces

• 2/3 of gas production in U.S• ½ OF gas production worldwide• Huge quantities of water used and waste water generated• Drilling and operating chemicals proprietary• Widespread watercontamination and health effects are reported

• Delays requirements for renewables•

Health effects attributed to fracking

• Aesthetics and outrage, noise and traffic• Toxics in local water supplies• Low birth weight babies related to timing of drilling

• Thanks to government loopholes, the oil and gas industry isn't required to disclose the chemicals they use -- but research has found that some known endocrine disruptors and carcinogens.

• A 2012 Pennsylvania ”gag law” forbids health care professionals from sharing information they learn about certain chemicals and procedures used in fracking

• NON-DISCLOSURE AGREEMENTS.

We are surrounded by electromagnetic radiation

We are assured, if not reassured that these waves are harmless

• As long as they are below the cooking threshold

Cell phones

5G tower

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Electromagnetic spectrumIONIZING ENERGY NON-IONIZING ENERGY

ELF

New 5G Network frequency Range

BELOW RADIO FREQUENCY

6 MHz to 6 GHzz

28 GHz to 68 GHz

Non-ionizing Radiation standard

• Non-ionizing radiation from oscillating electric and magnetic fields • 2011 IARC Group B2 “Possible human carcinogen” Based on thermal effect

• ELF: Extremely low frequency (including electricity, transmission lines)• 60 Hz

• MW: Microwave radiation Is absorbed near the skin (HEATING)• RF: Radiofrequency radiation may be absorbed throughout the body (can

also cause heating).• Sources of RF and MW radiation include radio emitters and cell phones

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Cancer epidemiology for non-ionizing radiation• Tony Miller, Iris Udasin, Devra Davis Environ Res. 2018 • Reviews epi studies published since the IARC 2011 2B Possible human carcinogen• RF: from mobile phones and other wireless devices as a possible human carcinogen• Glioma associated with RF in 9 case-control European• Ecologic studies show increase over time in UK and other countries• Non-malignant endpoints include acoustic neuroma (vestibular Schwannoma) and

meningioma in humans increased with cell phone use. • case-control studies can be superior to cohort studies or other methods in

evaluating potential risks for brain cancer.• Recommend reclassifying to GROUP 1 Human carcinogen

• Challenges: identify cohort, endpoint and exposure data

1999 Cell phones and cancer

• Cell phones and cancer: what is the evidence for a connection? - NCBI• by JE Moulder - 1999 – Radiation oncologist• “The epidemiological evidence for an association between RF

radiation and cancer is found to be weak and inconsistent,” • “the laboratory studies generally do not suggest that cell phone RF

radiation has genotoxic or epigenetic activity, and “• “A cell phone RF radiation-cancer connection is found to be physically

implausible.”

Survival and cancer in laboratory mammals exposed to radiofrequency energy.J. Elder joe.elder@Motorola.com

• Review effects of radiofrequency (RF) on (1). survival and (2). Cancer• 18 studies with survival data, and 16 of these have information on

cancer. • In one study, a significant decrease in lifespan at 6.8 W/kg but not at

2 W/kg. • Thermal stress appears to be the causal factor for the effect on

lifespan because the higher dose rate increases body temperature significantly. T

• low level exposure to RF energy does not adversely affect survival and cancer in laboratory mammals.

National Cancer Institute Fact Sheet:Cell Phones and Cancer Risk https://www.cancer.gov/about-cancer/causes-prevention/risk/radiation/cell-phones-fact-sheet [10-5-2018

• Brief reviews of many studies ranging from negative to inconclusive to weakly positive. • Hard to quantify exposure and exposure changed over time.• Contamination of control population by cell phone use

• INTERESTING EXAMPLE ANIMAL STUDY • It has been suggested that radiofrequency energy might affect glucose metabolism, but

two small studies that examined brain glucose metabolism after use of a cell phone showed inconsistent results.

• Whereas one study showed increased glucose metabolism in the region of the brain close to the antenna compared with tissues on the opposite side of the brain (2),

• the other study (3) found reduced glucose metabolism on the side of the brain where the phone was used.

National Toxicology Program---2 year studyrats and mice• Requested by FDA (current guidance based on heating)• Frequencies used in the US 2G and 3G networks• 10 min on/10 min off, 9 hrs/day• Significant increase of malignant gliomas & heart schwanomas in

males• Significant increases in non-cancer lesions in both sexes• This is NOT a negative or equivocal study• It is also not published in final form.

Electromagnetic hypersensitivity

• Early computer terminals elicited responses: headaches, buzzing noise, inability to concentrate.

• High-voltage transmission lines (Werthheimer & Leeper 1979)• Radar equipment (Robinette etal 1979) mortality• Some people identify symptoms related to certain EMF sources• Intolerant of using cell phone or nearby cell phone use• Wireless devices worse than hard-wired• Tests showed some couldn’t detect when field was on or off• Prevalence unknown

Typical clinical approach

• Examine individual’s mental model• Validate diagnosis • Help patient identify ways to avoid exposure• Help patient minimize physical symptoms

• Does medication help (antihistamines)

• Help patient minimize apprehension and anxiety• Cognitive behavioral therapy• Anxiolytics (chlordiazepoxide)

European guidelines for EMF sensitivity

• Scientific and Political debate• “While biophysical and biochemical mechanisms of low-intensity EMF

are not exactly known.”• Mixed exposure: mobile phones emit RF, VLF, ELF, & static fields • “EHS and MCS are genuine somatic pathological entities”• “Take all reasonable measures to reduce exposure to EMF/RF from

mobile phones, particularly children most at risk for head tumors.• Some effects apparent at low intensity exposure not apparent at high

intensity. • Resonance mechanisms not understood

Precautionary Principle• The cost of demonstrating that a product or policy is safe should be borne by

those who introduce the product or policy.

• Not by those who may suffer its consequences.

• Chemicals are not “innocent until provent guilty”.

• Better testing. • Better surveillance of impact.• Better investment in epidemiology.• Doesn’t replace risk assessment

GLOBAL ENVIRONMENTAL HEALTH• Urban air pollution (coal smoke, automobiles) kills about 1 million/yr• Rural air pollution (waste fires)• Indoor smoke kills 1.6 million due to respiratory disease• Unsafe water & poor sanitation 1.7 million (particularly infants)• Malaria kills 1.2 million (mostly children)• Drought vs water for irrigation• Deforestation and loss of biodiversity impacts subsistence societies• Urban air pollution kills about 1 million annually• Climate change (extreme weather, changing disease patterns)

Environmental Justice• Exposure to environmental hazards disproportionate for low income &

minority communities• Environmental racism a consequence of economic disparities• Mixed exposures (lead, low food security) impacts babies• Amplify this a thousand fold for EJ on a global scale • 15% of people suffer “hunger” and undernourishment• Socialists blame for profit food distribution (“there’s enough food”)• Ecologists ask “How many people can the earth support” • What is the carrying capacity (based on land, water, sunlight)• It depends on the chosen standard of living.

If we want to live like “Americans” Earth can’t support 7 billion people

Garrett Hardin“The Tragedy of the Commons”Science 13 December 1968: 162 no. 3859 pp. 1243-1248

• One of the most cited papers of the 20th century• Basic Premise:

Shared access to “common pool” resourcesfisheries, forests, minerals, arable land, water

Without control or regulationSubtractabiliityNo incentive for sustainabilityFish out your resource quickly and invest in the stock marketAnd sell your boats to another country so they can quickly deplete their fish

Dozens of efforts to “disprove” or provide exceptions

Global Population

• UN Population clock 7.65 billion 100,000 per day 1.2% per year• US Population 328 million 5800/day

• Most common estimate is leveling off at 9.5 billion by 2050• No mention of how the “leveling off” will be achieved

• Developing countries nearing 0% growth• So almost all of the 2 billion new mouths will be in countries with low food

security already• Ecological concept of “carrying capacity”. How many head per acre.

http://www.sos2006.jp/english/rsbs_summary_e/1-what-is-sustainability.html

10.5 billion

9.5 billion

7.5 billion

OPTIONSIncreasing the “pie”

Green revolutionImproved technology

More chemicalsOR

Restore US funding of international FP

Support education of girls