Glen Sampson

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.

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.

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.

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).

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.

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

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

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

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.

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

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.

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)

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

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%

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

Dose-Response The Swiss physician Paracelsus ( ), 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.”

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”

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

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)

Toxicological Studies

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

Developmental Toxicology

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.

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)

Classification of Pesticides LD or less Very Toxic Between 50 and 500 Toxic Between 500 and 5000 Moderately toxic > 5000 Low Toxicity

Examples of Acute oral LD 50 Nicotine 53 DDT 87 Paraquat 120 Caffeine 192 Fenitrothion 250 2,4-D 600 Table salt 4000 Glyphosate 4320 Chlorothalonil 8000 Bt 20,000

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

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

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.

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.

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.

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

Hazard assessment of 2,4-D At high doses 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 mg/kg body wt/day Not an environmental mutagen Not found to be carcinogenic in lab studies

Mandatory Incident Reporting Required by Pest Control Products Act. Any adverse incident must be reported, investigated and results published in the public registry spc/pubs/pest/_decisions/index-eng.php#rd-dh

Incident Report 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.

Incident Report 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.