Chemical and Physical agents of disease

Human Exposures to Environmental Hazards

* Chemical agents
* Heavy metals
* Electromagnetic radiation
* Ionizing radiation
* Air pollution
* Temperature increases from global climate change

Physical Agents of Disease

* Heat/Temperature
* Denature Proteins
* Hyperthermia/Hypothermia
* Noise
* Acute and Chronic Damage (hearing loss)
* Stress (doesn’t have to be loud to be stressful)
* Radiation
* Ionizing (causes mutations in DNA)
* Alpha particle & Beta Particle (size of neutrons, don’t penetrate well, but if breathed in can penetrate lung tissue and cause damage)
* Gamma & X-ray (size of electron, easier too penetrate, electromagnetic radiation, need lead to block)
* Non-ionizing
* Low energy UV light (sun light that penetrates ozone - can cause thymine dimers that can lead to cancer)
* Microwave (generate heat, can damage cells exposed to that heat)

Acute Exposure

short term exposure to large quantities

recovery possible if exposure is removed

Chronic Exposure

long term exposure to small antigens

not reversible when symptoms present

Metabolism/Excretion/Storage

* Mixed Function Oxidase (MFO’s) & Cytochrome P450
* enzyme systems to metabolize toxins for excretion
* sometimes metabolized to become toxic (ex. benzene)


* Metallothionins (macromolecules produced in body to remove metals)
* Kidneys (filters blood)
* Lungs (removes gas or vapor from blood)
* Skin (water or oils remove chemicals from skin)
* Bile Duct (from liver, fat soluble)
* discharged into small intestine and excreted
* Storage in lipids, tissue and bone

Routes of Exposure

how chemicals get in the body

–Penetration through the skin

–Absorption through the lungs

–Absorption through the gastrointestinal tract

–Injection

Particulates

small solid particles suspended in air that can be breathed in

–>0.01 and

Occupational Lung Diseases

•Silicosis - silica particles damage aveoli, lose lung capacity

•Pneumoconiosis (coal workers, black lung)

•Asbestosis - asbestis, can break up into small particles

•Occupational Asthma

•Byssinosis (cotton, flax, hemp)

•Chronic Obstructive Pulmonary Disease

* Permanent Condition
* Chronic Bronchitis
* Emphysema
* Asthma may lead to a permanent airway restriction condition

toxicity

the degree of harm that a substance can inflict

Toxicant

an substance with toxic properties

Toxin

a naturally produced toxic substance

\-produced by another organism

Ecotoxicology

•Effects of chemicals on the ecosystem

•Survival of humanity depends on the survival of other species.

•Ecosystem – network of interactions between physical, chemical and biological components within an area.

Environmental Toxicology

•The study of how toxic substances affect public health and the environment as well as the behavior of toxicants in the environment.

History of DDT

Late 1930’s – Muller’s discovery of the insecticidal properties of  dichlorodiphenyltrichloroethane (DDT) and several organohalides resulting in a wider use of insecticides.  DDT was first synthesized in 1874.

1930’s – discovery of sulfanilamide (antibiotic).

•Needed an effective delivery system

•Highly insoluble in an aqueous medium

•Prepared originally with ethanol (elixir)

•Later found that sulfanilamide was more soluble in diethylene glycol.

•Drug sold in the glycol solution but was still labeled “elixir”

•Several patients died of acute kidney failure

•Body metabolizes glycol into oxalic acid and glycolic acid which crystallize in the kidney tubules

•Resulted in Senator Copland’s Bill – titled Food, Drug and Cosmetic Act of 1938 (drug labeling, proof of drug safety, advertising and seizures of products by FDA)

•Sulfanilamide disaster lead to toxicological studies

Dr. Geiling

–Leaders in toxicology (started making it a science

–Focused on toxicology of **organophosphates**, **antimalarial drugs** and **radionuclides**

More on the History of epidemiology

•After World War II a growing concern for the environment and the effects from industrial development.

\
**Chemical industry developed rapidly**

* “Good life through chemistry”

\
**Chemical and Industrial waste disposal**

* buried chemicals leak out of barrels and start exposure to people

\
**Chemical fertilizers, pesticides**

•Better crop productions and control of insects

* Mosquito control and the use of DDT (NJ example)
* limit malaria as DDT lowered mosquito populations
* now use parathyroid as it breaks down faster at dusk to target mosquitos
* used to use persistent insecticides so that we didn’t have to keep applying, led to more exposure to untargeted insects and later people

\
All of these events between **1940** **and 1946** led to the **explosion in toxicology**.

•**Organophosphate** cholinesterase inhibitors discovered by **Willy Lang and Gerhard Schrader** later replaced DDT in the 1960’s

•Over time saw a **deterioration** of air and water quality

* Urban smog caused widespread fatalities
* Donora, PA (1948)
* London, England (1952)

Donora, Pennsylvania (1948)

5 day inversion
20 people died
Damp blanket of smoggy air with sulfur

\
coal burning creates sulfuric acid in the atmosphere leading to death when inhaled

Great London Smog - 1952 

•5 day period

•3000 excess deaths

•Caused by atmospheric inversion

–Cool surface air trapped by overlaying warm air

•Use of coal burning equipment

history of climate change reports

•1957, Roger Revelle and Hans Suess published a paper calling attention to atmospheric carbon dioxide increasing due to fossil fuels.

•July 1986 (29 years later) “Nature” magazine forecasted climate change from increase in CO2 and the “Greenhouse Effect.” 

DDT (Dichlorodiphenyltrichloroethane)

•**Widespread use** of DDT began during the **early 1940s** and reached a **maximum during the 1960s.**

•Due to concerns about the possible adverse effects upon the **health** of **humans and wildlife**, **application of DDT was prohibited in 1972 in the U.S**.

* especially bad for eagles as the DDT prevents calcium metabilation which led too soft eggs

•**Most developed** nations **banned** the use of **DDT**; however, **some countries** still **continue to use** DDT.

Facts about DDT

•**Not regarded as a highly toxic** pesticide

•Formerly **employed worldwide** to control **insects** and harmful **mosquitoes** that carry **malaria**

•Was **credited** at one time with **saving millions of people** from death due to **malaria**

•**Concentrates** in the adipose (**fatty**) **tissues** of the body

•Estimated **half-life** of approximately **10 years**

•**All living organisms on earth contain some** levels of this pesticide.

Human Health Effects of DDT

•Linked to:

–**Cancer** (pancreatic, non-Hodgkin’s lymphoma, and breast)

–**Reproductive effects**

–Impaired **lactation**

–**Falling sperm counts**

–Impaired **neurologic** function (irritability, dizziness, and numbness)

–Linked to Alzheimer's Disease

Biomagnification of DDT

concentrations of DDT increase as you go up the food chain

1960’s

•Tragic “**Thalidomide**” Incident

* drug used by pregnant women, led to malformed limbs of children

\
•Publication of “**Silent Spring**” by Rachel Carson

* Overuse of pesticides will eventually kill off the songbirds

\
•Toxicology started to look at teratogenic effects

\
•“**Dilution is the solution to pollution**”

* started pumping chemicals into rivers to dilute them out, incorrect as chemicals are persistent

\

•**Runoff** from fields containing fertilizers – **eutrophication**

•**Irrigation** of poorly drained fields lead to **salinization of land**.

Rachel Carson

1907-1964

Marine Biologist from Pennsylvania

MA from Johns Hopkins U.

Author of ‘Silent Spring’

Received much attention, because she wrote

     and presented scientific facts well

She was disturbed by the **widespread and indiscriminate** use of pesticides

Many of these pesticides were known to affect wildlife e.g. kill birds

She lobbied very hard to control and ban certain highly toxic chemicals

Testified before congress in 1963 and called for new policies with respect to human health and the environment

1970’s

•Love Canal

•Toxic Substance Control Act (TSCA)

* require testing of chemicals

•Federal Environmental Pesticide Control Act

* amended FIFRA – Federal Insecticide, Fungicide, and Rodenticide Act (required testing and lisencing of pesticides)

•What to do with chemical waste?

•Started to identify contaminated sites throughout the country

–Exposure to humans (air, water, soil, food)

–Contaminated sites originated mainly due to the improper disposal of hazardous chemicals (waste)

–Started to see effects on humans

•Chronic illnesses (organ diseases, cancers)

•Birth defects

Love Canal \n (Chemical Exposure/Effects)

–Love Canal located in Niagara Falls, NY

–Hooker Chemical - 265,000 tons waste, 1942-1953

–Donates site; town builds school and housing there in the 1950’s

–**Cancer cluster** - **4 x miscarriages**, **other diseases**

700 families relocated

Bhopal, India

•1984 accident discharged **methyl isocyanate** into the air from a Union Carbide pesticide manufacturing facility 

•One of the largest industrial accidents of the 20th century

•Overnight **death of approximately 4,000** individuals and over **100,000 injuries** (many thousand of the injured died later)

•Primary cause of death was **pulmonary edema**

•Many **survivors** showed signs of **compromised respiration** (e.g. bronchoalveolar lesions and decreased lung funtions) and **impaired vision**.

1980’s

•May 1985 – British research team reported levels of atmospheric ozone over the Antarctica had declined sharply. 

–Ozone hole

–UV Radiation and skin cancer

•July 1986 (Nature magazine) – CO2 and Greenhouse effect.

•New Jersey passes Toxic Catastrophe Prevention Act (TCPA)

* response to bhopal
* any airborne chemical needs to come up with plan to take care of release
* ex: chlorine gas was used to treat water, switched to liquid chlorine instead

CFCs and the Ozone “Hole”

chlorofluorocarbons are very stable molecules, could make their way up to stratosphere, then UV caused chlorine radicals to be released and break down ozone

\
refrigerators, aerosol spray cans, air conditioners were all sources of CFCs

Addressing the Ozone hole Problem

•Montreal Protocol:

* 1987
* > 180 nations signed (including USA)
* restricted CFC production globally
* strengthened by follow-up agreements

\
•Clean Air Act Amendments of 1990

* End of CFC Production (Jan. 1, 1996)

\
•Today

–CFC levels are down

–stratospheric ozone starting to recover

–Montreal Protocol appears to be a major environmental success

\
•We have apparently corrected a potentially major environmental problem

–government and industry cooperated on finding solutions

reasonable replacement technologies for CFCs

1989

Environmental Defense Fund (Mission Statement)  is a leading national nonprofit organization representing more than 700,000 members. Since 1967, we have linked science, economics and law to create innovative, equitable and cost-effective solutions to society's most urgent environmental problems.

\
•“Environmental Defense Fund” lists 8 most critical issues:

–Greenhouse effect

–Ocean pollution

–Protecting wildlife and habitat

–Recycling

–Saving the rain forests

–Acid rain

–Antarctica (Ozone hole)

Toxins (toxic substances)

International Regulation

•The Stockholm Convention on Persistent Organic Pollutants (2001)

–Calls for an end to the use and release of 12 POPs

* persistent organic pollutants the “dirty dozen” are primarily pesticides

__National Environmental Policy Act__

First piece of environmental legislation

–1970

–Created the EPA

–Initially 5000 employees (1970)

–Budget of 1.3 B

–In 1995 there were >18,000 employees, budget of 7.2 B

–USA is divided into 10 management regions

__Clean Air Act__

1970

–Required the EPA to set standards

–EPA in charge of controlling mobile and stationary emissions sources

–EPA controls hazardous pollutants

–Amended in 1977 to set compliance standards

–Amended again in 1990 to regulate acid rain and CFC emissions

__Federal Environmental Pesticide Control Act__

–1972

–amended FIFRA – Federal Insecticide, Fungicide, and Rodenticide Act

–Required manufactures to provide PMNs (Pre Manufacture Notice) with toxicological information to register a pesticide

F__ederal Water Pollution and Control Act__

–1972

–Provided sewage treatment plant grants for many municipalities

–Set effluent limits based on technology standards

–__Toxicity testing__ is used to set maximum allowable concentrations of toxicants in discharges and receiving waters

–Goal was to have __all water fishable and swimmable by 1983__

–Established goal to __eliminate pollution discharges by 1985__

__Safe Drinking Water Act__

–1974

–Set mandatory drinking water standards

–Controlled underground injection of wastes (aquifer protection)

–Amended in 1984 to set a schedule for establishing drinking water standards for 80 chemicals (provides notice to consumers)

__Toxic Substances Control Act__

–1976

–Regulated the use of chemicals in manufacturing and production

–Goal was to characterize the human health and environmental impact of **EVERY** chemical manufactured in the USA

–EPA has only 90 days to review and evaluate data

__Resource Conservation and Recovery Act__

–1976

–Controlled the disposal of solid waste

–Set new hazardous waste regulations

__Comprehensive Environmental Response, Compensation and Liabilities Act__

–Also known as __SUPERFUND__

–1980

–Provided funding mechanisms to clean up abandoned waste sites

–Amended in 1984 to ban ‘land disposal of hazardous waste

–Amended in 1986 to include requirements for community emergency plans and publication of corporate Toxic Release Inventories

–Established program to develop innovative approaches for cleanup and assessment of hazards

__Clean Water Act__

–1987

–sets national water quality standards

Toxicological (animal) testing of ‘xenobiotics’ is federally mandated by

–Federal Insecticide, Fungicide, and Rodendicide Act (FIFRA)

–Federal Environmental Pesticide Control Act

–Federal Water Pollution Control Act

–Safe Drinking water act

–Toxic Substances control Act

What is the extent of the problem?

•Thousands of chemicals are manufactured and released into the environment. (not all fully tested)

–Accidental release (e.g.. Oil spills)

–Released on purpose (e.g.. Pesticides and household products)

–Permitted discharges to air, water and soil

–historic disposal practices (to land and water)

•“Dilution is the solution to pollution” and “out of sight, out of mind”

•Jackson Twp. Aquifer (1972) contaminated (volatile organics) from disposal of toxic waste in the Municipal landfill.

•Van Dyk Research

•Rowe International

•Colloid Chemical

–Leaking underground storage tanks

\
•The toxicity of most of these compounds is unknown.

Concerns

•Occupational exposure

•Contaminated drinking water

•Hazmat spills – effect on responders and ecosystem

•Contaminated air, water, soil, food and biota

•Overuse of pesticides

Terrorism – chemical agents

Toxic Substances Formed in Nature (some examples):

•Red Tides

•Paralytic Shellfish Poisoning (PSP)

•Ciguatera

•Botulism Toxin and other microbial toxins

•Poison Ivy

•Venom

Evaluating Risk (Risk Assessment)

method for evaluating exposure

\
Source → Transport → Receptor

Source

•Occupational exposure

•Contaminated sites

•Spill

•Air/water discharge

•Natural (e.g. Radon, Arsenic)

Transport  (movement from sources to receptor)

•Soil

•Water

•Air

•Soil gases

•Food

Direct contact with source

Receptor

•Inhalation

•Dermal contact

•Ingestion

•Injection

Historical Transient Source/Exposure

Past exposure where the chemical is no longer present, effects still there

\
•**Past exposure** (i.e. air discharge) where source and contaminant is no longer present.  No current exposure.

•**Currently seeing effects** (clustering) of a possible  historical exposure.  However, current sampling efforts do not identify a possible causative agent.

•How does the epidemiologist and environmental toxicologist **reconstruct the historical exposure**? How accurate is the reconstruction?

* have to go to state records to see if measurement was ever made and try to reconstruct

Benefits of Chemical Use

•Increased food production

•Improved human health (pharmaceuticals)

•“Better living through chemistry”

Chemical Harm (Hazardous Chemicals)

•Explosive

•Flammable

•Corrosive

•Irritants

•Allergic Response

•Toxicity

–Poisons (LD50 of 50 mg or less per Kg body weight)

Poisons

LD50 of 50 mg or less per Kg body weight

LD50

lethal dose for 50% of specimen

\-measure toxicity through LD50

\-smaller the LD50 the more toxic

Hazardous Condition

•Must consider the probability of exposure to a hazardous chemical

Types and Mechanisms of Toxic Effects

•Carcinogens

•Mutagens

•Teratogens

•Immune effects

•Neurotoxins

Endocrine disruptors

Carcinogens

•Toxicants that cause cancer

•Causes uncontrolled cell growth and division

•Takes a long time for effects to occur (latency period of 10-20 years)

•Cigarette smoke is the most common carcinogen

•Historically considered the most important effect of toxicants

\
assumption is that any exposure can produce cancer, larger doses only increase the probability

Chemical-Induced Carcinogenesis (cancer) Is a Multistep Process

•***Initiation -*** the **genotoxic event** that leads to **mutations** of the DNA and places the affected cells at a greater risk for tumor formation.

•***Promotion -*** the second step in the carcinogenesis process, which moves initiated cells further along their transformation process. Exposure of initiated cells to **chemicals that stimulate cell proliferation**, such as irritating substances, results in the production of a clone of proliferating cells within the tissue.

•***Progression -*** Progression is the next step toward the transformation of cells into a tumor that is malignant. At this stage in the process, and depending on the particular tissue of origin of the cell, a **high growth rate and invasion** into surrounding tissue may occur.

Benign Tumor

tumor that stays within a structure

\
does not migrate to other parts of the body

Malignant tumor

tumor that has started migrating throughout body

\
cancer

mutagens

•Toxicants that cause a **change in the genetic sequence.**

•Can cause **cancer** or other disorders

•Mutations that affect **germ cells** can be **inherited**

•The most widely used **toxicity test (Ames test)** measures mutagenicity.

Mutations

Changes in the Base-Pair Sequence

\
lead to changes in protein expression

Teratogens

•Toxicant that causes harm to unborn children

•**Interferes with normal development**

•Causes **birth defects**

•**Thalidomide**

–Used as a sleeping pill and to treat nausea in pregnant women

–Caused limb deformities and organ defects

Allergens

–Toxicants that over-activate the immune system

–Damage is done by the body’s own defenses

–Asthma may be stimulated by environmental allergens

–**Hypersensitivity**

immune supression

–Some chemicals may **suppress** the body’s ability to fight infection

–**PERFLUOROOCTANE SULFONATE (PFOS)**

neurotoxins

•Toxicants that cause damage to the nervous system

•Can cause developmental problems

\
**Heavy metals**

–Lead, Mercury, Cadmium

\
**Pesticides**

–Organophosphates

–Organochlorides

\
**Nerve gas**

Sarin

endocrine disruptors

Toxicants that **interfere** with the normal functioning of the **body’s hormone system**

\
Often they are **toxic at very low concentrations**

\
They can affect:

–Reproduction

–Development

–Physiology

\-Behavior

Hormone Mimics

chemicals that look like hormones

\
bind to receptor, activates cell or block receptor

\
can also react with hormone to change structure

Potential Human Reproductive Effects

•Feminization

–Estrogen mimics

–Conversion of testosterone to estrogen

•Testicular Cancer

•Breast Cancer

•Un-descended testicles

•Genital birth defects

Neurological development

decrease in sperm count

Some endocrine disruptors

Pesticides

–DDT

–Endosulfan

–Methoxychlor

Highly Chlorinated Compounds

–PCB’s

–Dioxin

–Furans

Alkylphenols and Alkylphenol Ethoxylates

•Plastic Additives

–Bisphenol A

–Diethyl Phthalate

Di (2-ethylhexyl) Phthalate

Acute effects of chemical exposure

reversible

•Alteration of vital signs

•Abnormal skin color

•Abnormal skin odor

•Excessively dry or moist skin

•Miosis – contraction of the pupil

•Pupil dilation

•Conjunctivitis

•Gastrointestinal disorder

•Central Nervous System disorder

•Death

Chronic Effects to chemical exposure

Not reversible

•Mutation

•Cancer

•Birth defects

•Immunosuppression

•Gastrointestinal illness

•Hepatic disease

•Renal disease

•Neurological disorders

•Skin abnormality

•Bioaccumulation

•Body weight

•Fatty liver

•Death

Health Effects Associated with Work Environment

* Health risks for **pregnant workers** and the unborn fetus
* Various lung diseases
* Dermatologic problems
* Bladder cancer among dye workers
* 2 – naphthylamine
* Leukemia among workers exposed to benzene

The Healthy Worker Effect

•Observation that employed populations tend to have a lower mortality experience than the general population.

•The healthy worker effect may reduce the measure of effect for an exposure.

\
working population tends to be healthier

* cannot extrapolate exposure from workplace to rest of population

Difficulties

–Determining the **history of exposure**

–Understanding the effects of **combined exposure**

case histories of human toxicoloogy

–Study cases of poisonings

–Identifies the effects of acute and high-dose exposure

–Determine the lethal dose

Epidemiolody

–A statistical approach

–Addresses questions of probability and risk

–Uses a large sample size

–Measures the effect of long-term exposure

–Tests real-world conditions

–Looks at different end-points (more than just lethality)

–Hard to determine if the effects are caused by the condition being studied

–Cannot be used to predict the toxicity of new compounds before they are approved

–Descriptive Studies

–Case Control Studies

–Cohort Studies

Ecological Studies

Ecologic Study Designs

•One use is the study of the health effects of air pollution.

•Unit of analysis is the group, not individual

•Researchers measure the association between average exposure to air pollution within census tracts and the average mortality in those census tracts.

•Unable to controI for individual factors, e.g., smoking habits.

collection of exposure data

•**Employment records** often are used and may include:

–Personal identifiers to permit record linkage.

–Demographic characteristics.

–Work history.

–Information about potential confounding variables, e.g., medical history, smoking habits.

intervention studies

tests a potential drug, medical device, activity, or procedure

–Ethics of using human subjects

–Animal models

•Mice and rats are commonly used

–Mammals

–Similar physiology

•Other models

–Cell cultures

–Bacteria

Invertebrates

measuring toxicity

•**Toxicity** – The degree of harm that a substance can inflict.

•**Dose** – The amount of a toxicant received.

**Response** – The degree or type of effects

Acute dose-response analysis

–Administer different doses of a toxicant  to a large number of subjects and measure the response.

–Draw a “dose-response curve”.

LD50

“lethal dose” – the dose that results in the death of 50% of the subjects

–High LD50 means low toxicity

–Low LD50 means high toxicity

LC50

“lethal concentration” – the environmental concentration that leads to the death of 50% of the subjects

ED50

“effective dose” – the dose that results in a measurable effect in 50% of the subjects

**Threshold**

highest does of chemical where we see no effect

\
below line we see no effect, above we see effect

\
carcinogens have no threshold as it is assumed all levels can increase risk of cancer

Research questions

•**Relevance to humans**

–Will humans react the same as the model animal?

\
•**Safety Factor**

–Regulations are usually set well below the estimated toxic level

\
•**Variability**

\-within human population

\-not everyone will react the same

Variability

–Genetic differences

–History of exposure

–General health

–Gender

–Body size

\-Age – especially for the very young

What level of exposure is acceptable

•**Reference Dose**  (non-carcinogens)

* amount someone can be exposed to with no effect for chronic exposure

•**Risk** (carcinogens)

* what level will give a 1 in a million chance to get cancer

•Development of **standards** (food, water, air and soil)

Risk assessment

•Risk is a measure of how likely it is that a negative effect will take place.

•**Risk** = **Toxicity** (slope factor) X **Exposure**

•Total Exposure is determined by the __frequency__ and __length__ of individual exposures and the __concentration__ of the toxicant.

Acceptable Risk

•**New Jersey** = 1 / 1,000,000  or 10 -6 

•**Federal** = 1/ 100,000 or 10 -5

regulation of toxic compounds

**FDA**

–Food, Drug and Cosmetic Act

\
**EPA**

–Federal Insecticide, Fungicide and Rodenticide Act (FIFRA)

–Toxic Substances Control Act (TSCA)

–Resource Conservation and Recovery Act (RCRA)

\
**OSHA**

pesticides

Used to Control Pests

\
•Insecticides

•Herbicides

•Rodenticides

Four Classes of Insecticides

•Organophosphates - synapse - perminant

•Organocarbamates - synapse - temporary

•Pyrethroids - axon

•Organochlorides (organochlorines) - axon

examples of organochlorine pesticides (persistent)

•DDT

•Lindane

•Chlordane

•Mirex

•Hexachlorobenzene

•Methoxychlor

Examples of Organophosphates

•**Diazinon, malathion, methyl parathion, and parathion**

•Appear in a wide variety of products: sprays, baits, indoor foggers and bombs, flea collars, pet shampoos, powders, animal dips, and granules

•**Malathion has been approved for direct application to food crops** such as fruits (e.g., apples and grapes), row crops, and vegetables (e.g., tomatoes).

*Asbestos*

– a mineral fiber.

–Was used commonly for ship building, construction, insulation, and automobiles.

–Associated with asbestosis, mesothelioma, and lung cancer.