Introduction to Toxicology DR ERIC AMSTER INTRODUCTION TO

Introduction to Toxicology DR. ERIC AMSTER INTRODUCTION TO ENVIRONMENTAL AND OCCUPATIONAL HEALTH

Lecture Goals General introduction to toxicology Understand the relationship between mechanistic, descriptive, and regulatory toxicology Understand dose response curves and the difference between threshold and linear response Understand the relationship between toxicology and theprecautionary principle

What is Toxicology • Study of ways in which toxic chemicals (natural and synthetic) may cause negative effects in living organisms • “Living organisms”, includes man and animals (ecotoxicology) • “Negative effects”, includes effects on ability to function, reproduce, and survive • These effects can include obvious effects (vomiting, skin irritation, cancer) and subtle ones (effects on learning and memory)

Measures of Toxicity of chemicals is determined in the laboratory The normal procedure is to expose test animals 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

Measures of Toxicity is measured as clinical “endpoints” which include Mortality (death) Teratogenicity (ability to cause birth defects) Carcinogenicity (ability to cause cancer), and, Mutagenicity (ability to cause heritible change in the DNA)

Measures of Toxicity: The Median Lethal Dose LD 50 The amount (dose) of a chemical which produces death in 50% of a population of test animals to which it is administered by any of a variety of methods mg/kg Normally expressed as milligrams of substance per kilogram of animal body weight

Measures of Toxicity: The Median Lethal Concentration LC 50 The concentration of a chemical in an environment (generally air or water) which produces death in 50% of an exposed population of test animals in a specified time frame mg/L Normally expressed as milligrams of substance per liter of air or water (or as ppm)

LD 50 and. LC 50

Units Used to Measure Chemicals in the Environment PPM – Parts per million PPB – Parts per billion PPT – Parts per trillion

A simple cube 1 cubic meter in volume 1 m 1 m 1 m

Divide each 1 cc block into 1, 000 blocks 0. 1 cm on a side 1 cm 0. 1 cm x 0. 1 cm = 0. 001 cm 3 In 1 m 3 block 0. 001 cm 3 = 0. 001 cc or 1 ppb 1 cm

Important Relationship For water at STP (standard temperature [23 o. C] and pressure [15 psi]) 1 cc = 1 ml = 1 g

Which means that 1 liter of water = 1 kg 1 mg / kg = 1 ppm 1 mg / liter = 1 ppm A 100 kg person ingests 10 mg of a toxin. What is dose? 2. . 1 g of toxin is released into 10 liters of water. What is concentration? 1.

Primary Routes of Exposure to Pesticides There are three primary routes by which organisms are exposed to pesticides Oral Dermal Inhalation

Primary Routes of Exposure: Oral Exposure Any exposure to pesticide which occurs when the chemical is taken in through the mouth and passes through the gastrointestinal tract During oral exposure, although carried within the body, the pesticide is still outside of the body cavity

Primary Routes of Exposure: Dermal Exposure of the skin to a pesticide Most common route of human exposure With proper hygiene this type of exposure is generally not serious unless there is a specific, rapid toxicological effect (often eye effects) which is of concern

Primary Routes of Exposure: Inhalation Exposure Occurs when a pesticide is breathed into the lungs through the nose or mouth Significant route of exposure for aquatic organisms Not of toxicological concern until it crosses from the lung into the body (unless the chemical is corrosive)

Duration of Exposure Three terms are commonly used to describe the duration of dose(s) Acute Chronic Subchronic

Duration of Exposure: Acute Exposure Application of a single or short-term (generally less than a day) dosing by a chemical If toxic symptoms are expressed, they are referred to as symptoms of “acute toxicity”

Duration of Exposure: Chronic Exposure Expression of toxic symptoms only after repeated exposure to a chemical in doses regularly applied to the organism for a time greater than half of its life-expectancy If toxic symptoms are expressed, they are referred to as symptoms of “chronic toxicity”

Lecture Goals General introduction to toxicology Understand the relationship between mechanistic, descriptive, and regulatory toxicology Understand dose response curves and the difference between threshold and linear response Understand the relationship between toxicology and theprecautionary principle

Disciplines Within Toxicology Based on presentation from Dr. Tamar Berman, Ministry of Health

Descriptive Toxicology Toxicity testing (in laboratory animals/ in vitro), which provides information for safety evaluation and regulatory requirements Data is used to evaluate risks posed to humans and the environment from exposure to specific chemicals

Descriptive Toxicology Acute toxicity vs. Acute oral toxicity Acute dermal toxicity Acute inhalation toxicity Skin irritation Eye irritation Skin sensitization Sub-chronic toxicity

Descriptive Toxicology Define toxic outcome Genotoxicity Carcinogenicity Reproductive toxicity Neurotoxicity Organ specific pathology

Mechanistic Toxicology Identifying and understanding the cellular, biochemical, and molecular mechanisms by which chemicals exert toxic effects on living organisms Useful in demonstrating that an adverse outcome (e. g. , cancer, birth defects) observed in laboratory animals is directly relevant to humans

Regulatory Toxicology Involves the establishment of standards for the amount of chemicals permitted in ambient air, food, industrial atmospheres, and drinking water Often integrates scientific information from basic descriptive and mechanistic toxicology studies with the principles and approaches used for risk assessment

Integration of Disciplines: Example of Atrazine Herbicide with widespread agricultural and non – agricultural use in Israel 18 % detected 16 14 12 10 8 6 4 2 CB AL D CP A T D D TF RL RM PE PA TC BC P Z D SI M RA AT R D EN ET X M N D T CL EP H AC AL D N LI ET D B 0

Atrazine: Descriptive Toxicology

Atrazine: Mechanistic Toxicology Triazines have no intrinsic hormone activity and cannot support carcinogenesis on their own Mammary tumors in atrazine-treated female SD rats are a result of interaction between treatment and the process of normal aging in these test animals (elevated endogenous estrogen levels) It is highly unlikely this response bears any relevance to humans

Atrazine: Regulatory Toxicology The International Agency for Research on Cancer (IARC) classified atrazine: • 1991: possibly carcinogenic to humans • 1999: not classifiable as to its carcinogenicity to humans How does this effect the World Health Organization (WHO) drinking water standard? • World Health Organization (2006): standard is 2 ug/L based on neoplastic effects • WHO (2011): standard is 100 ug/L based on effects on noncarcinogenic effects

Lecture Goals Understand the relationship between mechanistic, descriptive, and regulatory toxicology Understand dose response curves and the difference between threshold and linear response Understand the relationship between toxicology and the precautionary principle

Dose – response relationship Relationship between exposure and effect, measured as change in response with change in dose Example of alcohol Response or effect increases with increase in dose

No-Observed-Adverse-Effect Level (NOAEL) q The highest exposure level at which there are no statistically or biologically significant increases in the frequency or severity of adverse effect between the exposed population and its appropriate control q Wherever possible, the NOAEL is based on long-term studies, preferably of ingestion in drinking-water. q NOAELs obtained from short-term studies and studies using other sources of exposure (e. g. , food, air) may also be used

Lowest-Observed-Adverse-Effect Level (LOAEL) The lowest exposure level at which there are statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control group.

LOAEL and NOAEL

Threshold Paracelsus 1493 – 1541 “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy. ”

Not all chemicals have a threshold Carcinogens Lead PM 2. 5 Organophosphate pesticides? Bisphenol A? Question to students: How many cigarettes do you think that you could smoke per day without harming your health?

A safe threshold for lead?

Lecture Goals Understand the relationship between mechanistic, descriptive, and regulatory toxicology Understand dose response curves and the difference between threshold and linear response Understand the relationship between toxicology and the precautionary principle

Precautionary Principle “When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically. ” Wingspread Conference (1998)

Toxicology and the Precautionary Principle • Toxicology - obtain information on risks BEFORE widespread exposure of humans • Toxicology data alone can support decision to list a chemical as likely or probable human carcinogen by the International Agency for Research on Cancer Source: Silbergeld E. Int JOccup Med and Env Health 2004

Insufficient Attention Paid to Variability: Life Stages For exposures sustained during early development, the most important issue is that 'the timing makes the poison. ’ The Faroes statement: Human health effects of developmental exposure to environmental toxicants, May 2007

Example of Methyl Mercury In many cases, the pregnant woman appeared completely healthy, despite carrying a baby who suffered congenital methylmercury poisoning (Takeuchi et al. 1964)

Insufficient Attention Paid to Genetic Variability • Inbred strain limit genetic variability in experimental toxicology • Genetic susceptibility is emerging as important predictor of disease in environmental health

Insufficient Attention Paid to Vulnerable Communities Increased underlying risk as result of exposure to additional risk factors - lack of quality water - exposure to contaminants from industry or waste sites - crowding - inadequate nutrition - lack of access to medical care

“Precautionary Toxicology” • Explore Variability: Genetic, Vulnerable Populations, Susceptible life stages • Model real world exposure scenarios: low level exposure to chemical mixtures • New approach to findings that aren’t definitive – lack of evidence of risk should never be interpreted as proof of safety • New ways of communicating findings to public and decision makers: calculation of confidence limits, measures of uncertainty should be incorporated Source: Grandjean P. Toxicology and Applied Pharmacology 2005.