Pesticide Toxicology

1. Pesticide Toxicology Glen Sampson

2. The Public Debate • The public perceives “pesticides” as a unique class of chemicals • more “dangerous” than chemicals in prescription and over-the-counter medications • more “toxic” than chemicals that occur naturally in food and the environment. • Pesticides are intentionally designed to be toxic to plant, animal, or microbial pests just as antibiotic drugs are intentionally designed to be toxic to specific disease bacteria. • Many natural chemicals in our food supply can also be toxic to living organisms.

3. Conclusions drawn by the scientific communities represent their best professional judgment based on many years of education, research, and experience. • It is impossible to test or prove safety under every imaginable scenario. • However, the overall testing program is comprehensive; • it examines the responses to pesticide levels much higher than humans or animals would normally encounter. • The public is expected to place confidence in scientific and regulatory professionals • As a society we are ill-informed on the mandatory, comprehensive evaluation process that precedes the registration of every pesticide product.

4. a common misperception is that pesticides can be classified as “safe” or “not safe.” • No chemical either natural (produced by plants or other organisms) or synthetic (produced by man), can be determined completely safe. • The effort to develop conclusive evidence of safety is ongoing, but absolute safety can never be guaranteed.

5. Toxicology • Toxicology is the scientific study of the harmful effects of chemicals on living organisms: humans, animals, and plants. • Toxicological testing evaluates: • whether short-term exposure to a pesticide will produce acute effects (e.g., eye and skin irritation, death) • whether long-term, continual exposure will cause chronic effects (e.g., impaired liver function, reproductive abnormalities, cancer).

6. Understanding the biological mechanisms that underlie effects observed in animals allows toxicologists and risk assessors to predict the chances of harm to human populations exposed to the pesticide. • Consideration of exposure levels and effects produced at specific doses is essential in determining toxicity.

7. Pesticide Toxicology • Factors that influence the effects: • Toxicity of the chemical • Dose • Length of exposure • Route of entry

8. Pesticide Risk • Toxicity • Ability of a chemical to cause injury • Depends on: • Dose • Exposure • Risk – Hazard • Probability that harm will result from given use of a chemical • Depends on: • Toxicity • Exposure

9. Pesticide Risk Low Exposure - Low toxicity Low risk Low Exposure - High Toxicity Moderate risk High Exposure - Low toxicity Moderate risk High exposure - High toxicity High Risk

10. Exposure • The duration and magnitude of exposure determine the severity of the poisoning. In other words, the increment of time during which exposure to the dose occurs (duration), plus the size and number of doses (magnitude) combine to determine the severity of the poisoning. • A pesticide will trigger an adverse response when a person is exposed long enough to a dose large enough to cause harm.

11. Toxicology Concerns • The degree of hazard which the compound (its metabolites) present to the spray operator, to consumers and to animals (domestic and others) • Operator • Acute toxicity • Skin and mucous membrane irritation • Sensitivity to repeated exposure • Consumer • Short term and long term studies • Teratogenicity, mutagenicity, neurotoxicity, carcinogenicity, reproduction, immunosuppression, endocrine disruption

12. Effect of the Chemical on the Animal • Species-Specific • Individual-Specific • Toxic effects can vary with the size, sex, age, and general health of the test animals.

13. Routes of Exposure • The site of exposure to the pesticide impacts the rate of absorption into the bloodstream, as well as its distribution pattern. • Ingestion or oral exposure • Inhalation or respiratory exposure • Dermal (through the skin ) or Ocular (through the eyes)

14. Movement Within the Bloodstream • transport of a pesticide within the body depends on whether the pesticide is absorbed through the skin, lungs, or GI tract. • Uptake by Organs, Tissues, and Cells • Metabolism Within Cells • Pesticides are subjected to chemical alterations by enzymes in the body. Metabolism takes place primarily in the liver. • Pesticide Storage Sites Within the Body • Pesticides may accumulate in body tissues, proteins, fat, and bone. • Excretion and Elimination From the Body

15. How Chemicals enter the body • Absorption • Through skin, eyes, ear canals • Most vulnerable areas • eye • groin area • absorbs 10x faster than forearm • 95% absorb through skin Body Part Amount Absorbed Eye 100% Groin area 100% Ear canal 47% Scalp 32% Abdomen 19% Foot 14% Palm of hand 12% Forearm 9%

16. How Chemicals enter the body • Inhalation • Breathing in dusts, mists, fumes • Ingestion • Through the mouth • smoking, eating, licking lips, blowing out nozzles • Injection • By veterinary needles, staples, nails, • High pressure fluids forced under the skin

17. Dose-Response • The Swiss physician Paracelsus (1493-1541), the father of toxicology, believed the relationship between dose and response to be inseparable. • Paracelsus asked, • “What is it that is not poison? All things are poison and nothing is without poison. The right dose differentiates a poison and a remedy.”

18. The specific point on the dose-response curve where the more susceptible animals are first affected by a pesticide dose is termed the threshold level: • LOEL – the lowest dose that produces a measurable response in the most sensitive animals. • NOEL - “no observed effect level”

19. Toxicology Studies • all pesticide active ingredients and product formulation containing the active ingredient undergo this testing. • Acute toxicity - how poisonous after single dose, short term exposure • Oral LD50 • Dermal LD50 • Inhalation LD50 • Eye irritation • Dermal Irritation • Skin sensitization (allergy) • Antidote

20. Toxicology Studies • Chronic Toxicity -adverse effects of repeated exposure over a long time. • Short term • 90 day oral • 90 day dermal • 90 day inhalation • 1 year feeding • Long term • 2 year chronic feeding • Lifetime oncogenicity (tumors - benign or malignant)

21. Toxicological Studies

22. Toxicology Studies • Reproduction • Teratogenicity (birth defects) • Mutagenicity (altering genes) • Carcinogenic • Neurotoxicity • Immunosuppresion • Endocrine disruption • Exposure studies

23. Developmental Toxicology

24. Reproduction studies • The effects of the pesticide on male and female reproductive processes, from egg and sperm production and mating through pregnancy, birth, nursing, growth and development, and maturation. • The studies are conducted through two generations of offspring—that is, three generations including the parents.

26. Measuring Toxicity • Acute • LD50 (mg/kg body weight) • LC50 • PPM (1ppm=1mg/L) • Chronic • No uniform measure for most • Cholinesterase levels • Organophosphates - irreversible (antidote - atropine) • Carbamates - reversible (antidote - atropine)

27. Classification of PesticidesLD50 • 50 or less Very Toxic • Between 50 and 500 Toxic • Between 500 and 5000 Moderately toxic • > 5000 Low Toxicity

28. Examples of Acute oral LD50 • Nicotine 53 • DDT 87 • Paraquat 120 • Caffeine 192 • Fenitrothion 250 • 2,4-D 600 • Table salt 4000 • Glyphosate 4320 • Chlorothalonil 8000 • Bt 20,000

29. Reversible vs. Irreversible • Reversible • if its effects subside or disappear when exposure ends. • Irreversible • adverse pesticidal effects persist even when exposure is eliminated

30. Other Effects of Toxicity • Local vs. Systemic • Immediate vs. Delayed • Additive vs. Antagonistic vs. Synergistic

31. Toxicity Characterized by Effect • Death is the ultimate toxic effect, occurring when critical bodily functions are altered or inhibited. • Irritation is observed when a pesticide affects cells of the skin or eye; • Skin sensitization is an allergic reaction following multiple exposures over a period of time. The initial exposure “sensitizes” the person, and subsequent exposures cause the individual to react to the chemical by developing a “rash.” • Mutagenicity (also called genotoxicity) results from a change in the genetic material of a cell. • a gene mutation that changes the DNA genetic code; • and a structural mutation that causes structural chromosome damage. Disruptions in genes or chromosomes can lead to diseases (including cancer) and birth defects. A mutagen is of concern when it damages egg or sperm cells, enabling the defect to be passed on to successive generations.

32. Toxicity Characterized by Effect • Tumours (also called neoplasms) are abnormal growths of tissue; • benign or malignant • 4 types of malignant tumours • Leukemias are cancers of red blood cells, certain white blood cells, and the tissues that produce these cells. • Lymphomas are cancers that affect organs of the lymphatic system, such as lymph nodes. • Sarcomas are cancers of connective tissues such as bone, muscle, and cartilage. • Carcinomas are cancers of the internal or external epithelial tissues.

33. Pharmacokinetics: Absorption,Distribution, Excretion, and Metabolism • Determine how a pesticide moves into, gets distributed within, and finally leaves the body. • The studies are designed to address several major areas of interest: • The quantity of pesticide absorbed; • The distribution of the pesticide in tissues, organs, blood, and urine; • The identity, quantity, and location of the major metabolites; • The ability of the pesticide to be stored in tissues and organs; • The routes of excretion; • The differences in the absorption, metabolism, excretion, and distribution of a pesticide when animals are administered single doses versus repeated doses, or small doses versus large doses.

34. Hazard Assessment • No observable effect level - NOEL • The highest dose that will cause no effect • Acceptable Daily Intake - ADI • 1/100 of the NOEL • Maximum Residue Limit – MRL • Maximum allowable residue in food or drinking water • Takes into account the toxicological acceptability of residue arising from practical use

35. Hazard assessment of 2,4-D • At high doses - 40-150 mg/kg body weight per day • Peripheral nerve damage, birth defects, fetal toxicity • NOEL • 20 mg/kg body weight/day • ADI • 1/100 (0.01) NOEL - 0.2 mg/kg body wt/day • Not an environmental mutagen • Not found to be carcinogenic in lab studies

37. Mandatory Incident Reporting • Required by Pest Control Products Act. • Any adverse incident must be reported, investigated and results published in the public registry • http://www.hc-sc.gc.ca/cps-spc/pubs/pest/_decisions/index-eng.php#rd-dh

38. Incident Report 2011-2572 • An incident report was submitted to the PMRA by Syngenta Crop Protection Canada on June 24, 2011 • an unknown product containing the active ingredient paraquat. • Involved the death of an adult male who had accidentally ingested some herbicide containing 37% paraquat. • The individual was landscaping at his home and mistook a container of the product for a water bottle. • He was hospitalized for five days and treated for renal failure and pulmonary fibrosis. On the fifth day he was removed from life support and passed away.

39. Incident Report 2011-2572 • The effects reported are highly consistent with paraquat poisoning. Based on the estimated volume ingested, the individual likely received a lethal dose of paraquat. • The specific product implicated in this incident is not known. There are no products currently registered in Canada containing 37% paraquat, and products containing paraquat are not permitted to be sold to the general public. • This incident resulted from the accidental ingestion of a pesticide. The individual affected should not have had access to the pesticide involved and it is not known how the product was obtained in this case.