NUTR 4510 Synthetic Pesticides PDF

NUTR*4510 Toxicology, Nutrition & Food Unit 8: Synthetic Pesticides  Synthetic Pesticides in the Environment Bioaccumulation & can enter the food supply → LEVELS ARE MONI...

NUTR*4510 Toxicology, Nutrition & Food Unit 8: Synthetic Pesticides  Synthetic Pesticides in the Environment Bioaccumulation & can enter the food supply → LEVELS ARE MONITORED!!!! Pesticide residues can: - remain on fruits/veg and be consumed - Spread from fields into water supply or soil - Can be found in produce, meat, fish, dairy Synthetic pesticides → direct application to crop Health Canada approves all pesticides used in the food supply & assesses risk to humans  Pesticides in the Canadian Food Supply is STICTLY MONITORED Additional Imported & REMOVED from Canadian Produced follow up Food supply Foods monitoring to ensure safety 90% 9% 1% Maximum Residue Limits (MRL) → often several hundred times LOWER than the level found to cause harm in test animals Monitoring of MRL’s in the food supply is conducted by the Canadian Food Inspection Agency Health Canada is responsible for the pesticide residue monitoring program…to ensure any residues are well-below permitted limits Public concern about these residues (if any) posing a risk to human health & the potential interactions between different pesticides used on foods  NOT TESTED; For Interest (top only) IS TESTED ↓ Canadian Organic Food Products → What to Look For Canadian Organic Agricultural Products should have this logo  Synthetic Pesticide Toxicity Common victims: - Agricultural employees - Pesticide industry employees - Home accidents, especially children - Suicides (largest fraction of victims in some studies) * Study results related to pesticides and toxicity that alarm the public are often based on these victims, but their exposures do not compare to the general public Synthetic pesticide types: All pesticides used in Canada must be A. Insecticides evaluated and then approved by B. Herbicides Health Canada's Pest Management Regulatory Agency (PMRA). C. Fungicides Natural pesticide types: (discussed already) The Canadian Food Inspection 1. Nicotine Agency (CFIA) residue monitoring program provides further assurance of 2. Glucosinolates the safety of Canadian produce. 3. Cyanogens 4. Glycoalkaloids 5. Protease inhibitors 6. Etc.  Synthetic Pesticide Types A. Insecticides (BIG families of chemicals) - Almost all are neurotoxins 1. Organochlorines → activate the PXR (now BANNED) i. Dichlorodiphenyltrichloroethane (DDT) → metabolized by CYP6A2; 6G1 - Sodium (Na+) channel blocker – inhibits neuron depolarization, and therefore, the transmission of nerve impulses. This causes paralysis and eventual death - Bioaccumulates in the food chain - Estrogenic, leading to small increase in breast cancer risk - Banned in almost all countries but still necessary for protection against malaria in some countries ii. Aldrin, dieldrin, chlordane → metabolized by CYP2B and CYP3A enzymes - Chloride (Cl-) channel blocker – inhibit neuron hyperpolarization, and therefore, (Still in use) increase transmission of nerve impulses. This causes involuntary muscle movements - Lower bioaccumulation in the food chain compared to DDT 2. Carbamates and Organophosphates - Acetyl cholinesterase inhibitors (like solanine in potatoes) – cause hyperactive cholinergic synapses and may cause birth defects - Applied directly to plants or the soil - Highly toxic to marine life and decrease reproduction in marine bird species (some bioaccumulation in the food chain) - Degradation in environment is variable (can persist on a scale for hours → months, depends on the specific chemical) - E.g. Carbaryl → neurotoxic if accumulates OR metabolized by MULTIPLE CYP Enzymes - CPY1A1, CYP2E1, CYP2D6 (and many other CPY2 family members), CYP3A4 - Environmental Protection Agency (EPA) has identified Carbaryl as a “likely human carcinogen”  Synthetic Pesticide Types Insecticides - continued - Almost all are neurotoxins 3. Pyrethroid Insecticides → CYP 9 family (mostly) - From chrysanthemum flowers - Na+ / Potassium (K+) ATPase inhibitor –inhibits neuron repolarization, and therefore, the transmission of nerve impulses. Can cause paralysis and eventual death B. Herbicides - E.g. Phenoxy compounds [e.g. 2,4-Dichlorophenoxyacetic acid (2,4- D)]: Selectively kills most broadleaf weeds by causing uncontrolled growth in them, but leaves most plants relatively unaffected - Suggested to cause small increase in Non-Hodgkin lymphoma in agricultural and pesticide industry employees (examples of “occupational exposures or settings”) - Listed as a “possible carcinogen” - metabolized by CYP1A1/1A2…uses glucuronidation & glutathione conjugation for phase II According to Health Canada, the most common herbicide used in Canada = Glyphosate - used in weed management (i.e., invasive weeds and toxic plants such as poison ivy) in agriculture and non-agricultural land management INHIBITS the enzyme EPSP synthase, the rate-limited step in the synthesis of aromatic amino acids in the shikimate pathway in plants. Pathway not active in humans BUT ACTIVE IN BACTERIA!!  A Little More on Glyphosates… According to Health Canada: < 1-2% Readily absorbed if inhaled 2/3’s (~66%) lost in feces following oral exposure. The remainder is excreted in the urine as the parent compound. Minimal topical absorption. No tissue accumulation - Glyphosate levels identified in Canadian Retail Markets (2015 and 2017) was 0.6% of samples. Risk is VERY LOW and showed no risk to human health Scientific Literature: Short-term studies in rodents have shown no apparent toxicity Life-long exposure in rodents have demonstrated liver and kidney dysfunction, increased risk of cancer, and shortened lifespan Female rats are highly susceptible to mammary tumors following chronic exposure to glyphosate Toxic to Enterococcus, Bacillus and Lactobacillus species → leads to an imbalance in the microbiome that favours overgrowth of Clostridium species Pathogenic strains of Salmonella and Clostridium are highly RESISTANT to glyphosate Pseudomonas species can break down glycophosates to produce usable phosphate and carbon for amino acid synthesis BUT also produce formaldehyde as a toxic bi-product  Synthetic Pesticide Types C. Fungicides - E.g. Captan part of the of phthalimide family of fungicides - Induces expression of and can be metabolized by CYP1A1/1A2 and CYP3A1/3A2. Metabolism is complex, multi-step and involves glutathione conjugation reactions (amongst other types of reactions). Limited available human data (obviously). - Reduces mycotoxin contamination of fruits and vegetables - Easily penetrates soil and can enter the ground water - Caused intestinal tumors in mice (administered Captan by gavage) and was identified as a “probable human carcinogen” by the Environmental Protection Agency (EPA). - The EPA changed their classification system in 2004 and revised Captan to be “not likely” a carcinogen because the dose required to cause tumors was several orders of magnitude higher than the dose encountered in occupational settings.  SIMPLIFIED Captan Metabolism Captan is unstable in aqueous solutions degrading rapidly into thiophosgene (a highly reactive and short-lived toxic species), and tetrahydrophthalimide (THPI), a species considered to be non-toxic. GSH Other metabolites GST MANY other metabolites can be formed + cysteine Thiophosgene can react or with cellular thiols as well GSH as other functional groups (amines, amides, alcohols) OR undergo rapid degradation Thiazolidine-2-Thione-4-Carboxylic Acid (TTCA) THIP and TTCA levels in the urine are used as biomarkers of Captan exposure  DEET (Diethyltoluamide…who hasn’t used this/been exposed?) the most common active ingredient in insect repellents…providing protection against mosquitoes, ticks, fleas, and many biting insects. Varying levels in commercially available insect repellents…do YOU follow the instructions for application/safe exposures?? Metabolized by MULTIPLE CYP enzymes…allows for rapid phase I and production of intermediates. Signs of Toxicity → irritation, redness, rash, swelling AND after ingestion → oral irritation, nausea, vomiting CYP2E1 CYP2C19 CYP1A1/1A2 CYP3A4 CYP2B6 CYP3A5 CYP2A6 Phase 2: glucuronidation Excretion of glucuronide conjugates in the urine