Transcript Pesticide Toxicology - Plant Health Atlantic

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:
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Dose
Exposure
 Risk – Hazard
 Probability that harm will result from given use of a chemical
 Depends on:
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
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 (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.”
 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
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90 day oral
90 day dermal
90 day inhalation
1 year feeding
 Long term
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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
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
Organophosphates - irreversible (antidote - atropine)
Carbamates - reversible (antidote - atropine)
Classification of Pesticides
LD50
 50 or less
 Between 50 and 500
 Between 500 and 5000
 > 5000
Very Toxic
Toxic
Moderately toxic
Low Toxicity
Examples of Acute oral LD50
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Nicotine
DDT
Paraquat
Caffeine
Fenitrothion
2,4-D
Table salt
Glyphosate
Chlorothalonil
Bt
53
87
120
192
250
600
4000
4320
8000
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.
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
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
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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 - 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
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/cpsspc/pubs/pest/_decisions/index-eng.php#rd-dh
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.
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.