Pesticide Toxicology

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Pesticide Toxicology

• Glen Sampson

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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.

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• 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.

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• 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.

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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).

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• 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.

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Pesticide Toxicology

• Factors that influence the effects
• Toxicity of the chemical
• Dose
• Length of exposure
• Route of entry

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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

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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
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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.

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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

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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.

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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)

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• 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

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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
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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

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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.

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• 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

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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

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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)

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Toxicological Studies
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Toxicology Studies

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

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Developmental Toxicology
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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 offspringthat is, three generations including
  the parents.

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Measuring Toxicity

• Acute
• LD50 (mg/kg body weight)
• LC50
• PPM (1ppm1mg/L)
• Chronic
• No uniform measure for most
• Cholinesterase levels
• Organophosphates - irreversible (antidote -
  atropine)
• Carbamates - reversible (antidote - atropine)

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Classification of PesticidesLD50

• 50 or less Very Toxic
• Between 50 and 500 Toxic
• Between 500 and 5000 Moderately toxic
• gt 5000 Low Toxicity

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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

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Reversible vs. Irreversible

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

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Other Effects of Toxicity

• Local vs. Systemic
• Immediate vs. Delayed
• Additive vs. Antagonistic vs. Synergistic

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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.

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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.

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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.

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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

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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

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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/_decision
  s/index-eng.phprd-dh

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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.

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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.