Toxicology for Activists

8/12/2019 Toxicology for Activists

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Toxicology for Activists

Romeo F. Quijano, M.D.Professor, Dept. of Pharmacology and Toxicology,

College of Medicine, Univ. of the Phils. ManilaPresident, Pesticide Action Network PhilippinesPresident, Health Action for Human RightsBoard Member, Institute for Occupational Safety,

Health and DevelopmentMember, Phil Soc Clinical Occupational ToxicologyFormer Co-chair, International POPs Elimination Network


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Introduction

CULTURAL

ECONOMICPOLITICAL


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General Remarks

Toxicology is influenced by political,economic, and cultural factors.

Power relations largely determine thetoxicology agenda.Toxicology today serves mainly the

privileged class, the rich and thepowerful.


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Politics of Toxicology

Scientific Advisory Committee removedinstead of harmful pharmaceuticals.

Toxicology committee phased-outinstead of highly toxic pesticides.Harassment suits by Big Corporations.

Corporate funding of scientificresearches in academic andgovernment institutions.


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Politics of Toxicology

Most toxicologists are in the employ ofTNCs or TNC influenced institutions.

Most scientific journals controlled orinfluenced by Big Corporations.

UN bodies dealing with chemicals arehighly influenced by big business orgovernments protecting big business.


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Box plot (log) concentrations (pg/m3) of OCPs and PCBs at 38 sites


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What is Toxicology?

The study of the adverseeffects of toxicants on livingorganisms

The Study of Poisons


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Key words in Toxicology

Adverse effects Any undesirable change from a living

organisms normal state

Toxicant (Poison) any agent capable of producing a

deleterious response in a living

organism Living organism

Plants or animals, including micro-

organisms and humans


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Sub-disciplines of Toxicology Environmental Toxicology Occupational (Industrial) Toxicology Regulatory Toxicology

Food Toxicology Clinical Toxicology Descriptive Toxicology

Forensic Toxicology Analytical Toxicology Mechanistic Toxicology


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What is a Poison?

All substances arepoisons; there is none

that is not a poison.The right dose

differentiates a poisonand a remedy.

- Paracelsus (1493-1541)


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CHEMICAL CATEGORIES

Industrial chemicals(Petrochemicals, plastics, solvents,inorganic chemicals, heavy metals,

industrial gases,etcAgrochemicalsPersistent Organic Pollutants(POPs)

PharmaceuticalsChemicals in consumer products

Naturally occurring chemicals


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Exposure to Poisons Routes and Sites of Exposure

Ingestion (Gastrointestinal Tract) Inhalation (Lungs) Dermal/Topical (Skin) Injection

intravenous, intramuscular, subcutaneous Typical Effectiveness of Route of

Exposure: injection > inhalation >ingestion > topical


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Exposure: Duration Acute < 24hr usually 1

exposureSubacute 1 month repeated dosesSubchronic 1-3mo repeated dosesChronic > 3mo repeated doses

Over time, the amount of chemical in thebody can build up, it can redistribute, orit can overwhelm repair and removalmechanisms


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Acute Toxicity Studies

Single dose - rat, mouse(5/sex/dose), dog, monkey

(1/sex/dose) 1-14 days observation Record body wt., food and water

consumption, clinicalobservations(toxidrome)

Necropsy(gross observation of keyorgans)


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Repeated dose studies (usually 14days) - rat, mouse (5-10/sex/dose),

dog, monkey (2/sex/dose) Clinical observations Necropsy Histopathology Clinical pathology (optional)


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Subacute Toxicity

28 day study (3 doses and control) Species - rat (10/sex/dose), dog or

monkey (2/sex/dose) Clinical observations Clinical pathology Necropsy Histopathology


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Subchronic Toxicity 13 week study +/- 4 wk recovery (3 doses

and control)

Species - rat (10/sex/dose), dog or monkey(2/sex/dose) Clinical observations Clinical pathology Necropsy Histopathology Used to set doses for carcinogenicity

studies


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Chronic Toxicity

1 year study +/- 4-13 wk recovery (3doses and control)

Species - rat (10-15/sex/dose), dog ormonkey (2-3 /sex/dose) Clinical observations

Necropsy Histopathology


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Single dose - rat, mouse(5/sex/dose), dog, monkey

(1/sex/dose) 1-14 days observation Record body wt., food and water

consumption, clinicalobservations(toxidrome)

Necropsy(gross observation of key

organs)


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Repeated dose studies (usually 14days) - rat, mouse (5-10/sex/dose),

dog, monkey (2/sex/dose) Clinical observations Necropsy Histopathology Clinical pathology (optional)


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Subacute Toxicity

28 day study (3 doses and control) Species - rat (10/sex/dose), dog or

monkey (2/sex/dose) Clinical observations Clinical pathology Necropsy Histopathology


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Subchronic Toxicity 13 week study +/- 4 wk recovery (3 doses

and control) Species - rat (10/sex/dose), dog or monkey

(2/sex/dose) Clinical observations Clinical pathology Necropsy Histopathology Used to set doses for carcinogenicity

studies


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Chronic Toxicity

1 year study +/- 4-13 wk recovery (3doses and control)

Species - rat (10-15/sex/dose), dog ormonkey (2-3 /sex/dose) Clinical observations

Necropsy Histopathology


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Risk Characterization

Provides an overall conclusion andconfidence of risk for the risk manager

Gives the assumptions made

Attempts to Explain the uncertainties

Outlines the data gaps


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HumanEPI

Data

Where the

Question ofHealth Risk is

Raised

e s p o n s e

Log Dose

Paustenbach (1995)

AnimalData


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Units Used to MeasureChemicals

in the Environment

PPM Parts per million

PPB Parts per billion

PPT Parts per trillion


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Important Relationship

For water at STP (standard temperature[23 oC] and pressure [15 psi])

1 cc = 1ml = 1g


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Which means that

1 liter of water = 1 kg

1 mg / kg = 1 ppm

1mm 3 / liter = 1 ppm

1 mg / liter = 1 ppm


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Measures of Toxicity

Toxicity of chemicals is determined in thelaboratory

The normal procedure is to expose testanimals By ingestion, application to the skin, by inhalation,

gavage, or some other method which introduces

the material into the body, or By placing the test material in the water or air of

the test animals environment


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Measures of Toxicity

Toxicity is measured as clinical endpointswhich include

Mortality (death) Teratogenicity (ability to cause birth defects) Carcinogenicity (ability to cause cancer), and, Mutagenicity (ability to cause heritible change in

the DNA) At this time we will discuss 2 measures of

mortality the LD 50 and the LC 50


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Measures of Toxicity:

The Median Lethal DoseLD 50

The amount (dose) of a chemical whichproduces death in 50% of a population of testanimals to which it is administered by any of a

variety of methods

mg/kgNormally expressed as milligrams of substance

per kilogram of animal body weight


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Measures of Toxicity:The Median Lethal

ConcentrationLC 50

The concentration of a chemical in anenvironment (generally air or water) whichproduces death in 50% of an exposed

population of test animals in a specified timeframe

mg/LNormally expressed as milligrams of substance

per liter of air or water (or as ppm)


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DoseThe amount of chemical entering the bodyThis is usually given as mg of chemical/kg

of body weight = mg/kg

The dose is dependent upon* The environmental concentration* The properties of the toxicant* The frequency of exposure* The length of exposure* The exposure pathway


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Threshold Dose

A dose or exposure levelbelow which harmful oradverse effects are notexpected to occur.


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Maximim Tolerated Dose

The Maximum Tolerated Dose is

defined as the highest dose of achemical or drug that can beadministered for the animals life

without causing excessive toxicity ordecreasing survival.


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No Observed Adverse Effect

Level(NOAEL)An exposure level at which there areno statistically or biologically significant

increases in the frequency or severity ofadverse effects between the exposedpopulation and its appropriate control;

some effects may be produced at thislevel, but they are not considered asadverse, or as precursors to adverse

effects. - USEPA


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Dose-Response

Assessment The relationship between dose and

response

Two sets of data are usually available Data in the observable range Extrapolation to responses below the

observable range


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Exposure Assessment

EPA uses the cumulative dosereceived over a lifetime

This is expressed as the averagedaily exposure

Occupational exposures are usuallybased on exposure during the workweek


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K W d


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Key Words

Risk =Hazard X Exposure

Dose / Response

Individual Sensitivity

What is a Response?


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What is a Response?

Change from normal state could be on the molecular, cellular, organ,

or organism level signs and symptoms

Local vs. Systemic Reversible vs. Irreversible Immediate vs. Delayed Graded vs. Quantal

degrees of the same damage vs. all ornone


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Dose-Response Relationship: As the dose of a toxicant increases,

so does the response.

2

3

4

0 1 DOSE

RESPONSE

0-1 NOAEL2-3 Linear Range4 Maximum Response

DOSE DETERMINES THE BIOLOGICAL RESPONSE


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LD50 Quantal responses can be treated as

gradient when data from a population isused.

The cumulative proportion of the

population responding to a certain dose isplotted per dose

If Mortality is the response, the dose that is

lethal to 50% of the population (LD 50 ) canbe generated from the curve

Different toxicants can be compared--

lowest dose is most potent


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LD50 Comparison

Chemical LD50 (mg/kg)Ethyl Alcohol 10,000

Sodium Chloride 4,000Ferrous Sulfate 1,500Morphine Sulfate 900Strychnine Sulfate 150 Nicotine 1


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Ab i Di ib i


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Absorption, Distribution,Metabolism, and Excretion

Once a living organism has beenexposed to a poison, the compoundmust get into the body and to its target

site in an active form in order to causean adverse effect. The body has defenses:

Membrane barriers passive and facilitated diffusion, active

transport Biotransformation enzymes, antioxidants Elimination mechanisms

Absorption: bili f h i l h


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Absorption: ability of a chemical to enter theblood (blood is in equilibrium with tissues)

Inhalation-- readily absorb gases into theblood stream via the alveoli. (Large alveolarsurface, high blood flow, and proximity ofblood to alveolar air)

Ingestion-- absorption through GI tractstomach (acids), small intestine (long contacttime, large surface area--villi; bases and

transporters for others) 1st Pass Effect (liver can modify)

Dermal-- absorption through epidermis(stratum corneum), then dermis; site andcondition of skin


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Distribution: the process in which a chemicalagent translocates throughout the body

Blood carries the agent to and from itssite of action, storage depots, organs oftransformation, and organs of

elimination Rate of distribution dependent upon

blood flow characteristics of poison (affinity for the

tissue, and the partition coefficient) Distribution may change over time

T O


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Target Organs Not all organs are affected equally

greater susceptibility of the target organ higher concentration of active compound

Liver-- high blood flow, oxidative reactions Kidney-- high blood flow, concentrates chemicals Lung-- high blood flow, site of exposure Neurons-- oxygen dependent, irreversible damage Myocardium-- oxygen dependent Bone marrow, intestinal mucosa-- rapid cell

division


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Toxic Hepatitis


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Liver Cirrhosis


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Liver Cancer


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Kidney Cancer

T g t Sit M h i f A ti


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Target Sites: Mechanisms of Action Adverse effects can occur at the level of

the molecule, cell, organ, or organism Chemicals can interact with:

Proteins, Lipids, DNA, etc. Chemicals can:

interfere with receptor-ligand binding interfere with membrane function interfere with cellular energy production bind to biomolecules disturb homeostasis

Excretion: Toxicants are eliminated


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Excretion: Toxicants are eliminatedfrom the body by several routes

Urinary excretion water soluble products are filtered out of the blood

by the kidney and excreted into the urine Exhalation

Volatile compounds are exhaled by breathing Biliary Excretion via Fecal Excretion

Compounds can be extracted by the liver andexcreted into the bile. The bile drains into thesmall intestine and is eliminated in the feces.

Milk, Sweat, Saliva, Tears

Metabolism


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Metabolism The process by which the administered

chemical (parent compounds) are modified bythe organism by enzymatic reactions.

1o objective--make chemical agents morewater soluble and easier to excrete

decrease lipid solubility--> decrease amount at target

increase ionization--> increase excretion rate --> decreasetoxicity

Bioactivation-- Biotransformation can result inthe formation of reactive metabolites

Bi f i


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Biotransformation

Key organs in biotransformation LIVER (high) Lung, Kidney, Intestine (medium)

Others Biotransformation Pathways

* Phase I--make the toxicant more watersoluble

* Phase II--Links with a soluble endogenousagent (conjugation)

Individual Susceptibility


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p y there can be several fold differences in

responses to toxicants in a population Genetics - species, strain variation,

interindividual variations (yet still canextrapolate between mammals--similarbiological mechanisms)

Age In young, underdeveloped metabolic,

excretory, and other defense mechanisms In elderly, diminished defense capacity

Gender


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Thyroid Cancer


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Individual Susceptibility

Previous or Concurrent Exposures additive --antagonistic synergistic

Nutritional status Health conditions Social Determinants of Health


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MALNUTRITION

Malnutrition has notdeclined significantlyduring the past 20

years from 34% in1990 to 32% in 2001.

16.5M Filipinos go

hungry daily and 15MFilipinos eat onlyonce a day


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Basic Indicators

There are 297 cases ofTB per 100,000population; 48 deathsper 100,000 per year

(http://www.stoptb.org/countries/GlobalReport2006/phl.pdf)


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Hi hl H d


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Highly HazardousChemicals

Chemicals which are Widely produced

Widely transported Widely stored

High level of toxicityVaporize easily


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WHO Hazard Classification

Class Ia Extremely hazardous

Class Ib Highly hazardous

Class II Moderately hazardous

Class III Slightly hazardous

Class IV - Not hazardous under recommendedconditions of use


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01/26/09 POPs and Health 75

What are POPs?

POPs (Persistent Organic Pollutants),are carbon-based chemical compoundsthat are highly toxic, remain for a longtime in the environment, accumulate in

living organisms and travel longdistances in air and water.

The 12 initial POPs for early global

action include: aldrin, dieldrin, endrin,chlordane, DDT, heptachlor, mirex,toxaphene, HCB, PCBs, dioxins, andfurans .

PESTI IDE POISONINGS


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PESTI IDE POISONINGS

In the South, anestimated 25millionagriculturalworkers maysuffer oneincident ofpesticidepoisoning eachyear.

d


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Food Contaminants

Agrochemicals ( Insecticides, herbicides,fungicides , growth regulators , etc.)

Other environmental contaminants (radionuclides, heavy metals, PAH, Dioxins,PCBs, PFOA, PBDEs, BisphenolA, etc)

Food additives (nitrates, sulfates,colors,etc .)


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WHAT NEEDS TO BE DONE?

Stop intrusive and exploitativeglobalization policies that destroy localcommunities, take WTO out of agriculture.

Develop an alternative trading system thatfocuses on people to people exchanges.

Protect the rights of indigenouscommunities.


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What Needs to be Done?

Protect the rights, health and well-being ofagricultural and industrial workers.

Resist agrochemical TNCs.

Ensure genuine food security andsustainable agriculture.

Arouse, organize and mobilize

communities against exploitative corporateglobalization. Promote people empowerment.


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RESIST !

Corporate ScienceS ervingC orporateI nterest

E ngaged inN on-essentialC ommercialE xploits


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UPHOLD !

SCIENCE FOR THE PEOPLE

S erving

C ommunityI nterest

E ngaged inN oteworthyC reativeE ndeavors

Precautionary Principle


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Precautionary Principle

When there are reasonable groundsto indicate potential harm to health

& environment, precautionaryaction should be taken even ifcause and effect relationship has

not been established scientifically.- Wingspread statement, 1998


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What needs to be done?

A wareness raisingN etworking among groups

T echnical capacity building I nformation exchange/monitoringD eepening of understanding

O rganizing concerned peopleT ransformative actionE mpowerment of people


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Toxicology for Activists

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