HERBICIDES: Diphenyl Ethers And Developmental Toxicity
Jan 13, 2016
HERBICIDES:
Diphenyl Ethers
And
Developmental Toxicity
DIPHENYL ETHER HERBICIDES• Contact herbicides
– Readily absorbed by roots, leaves– Limited translocation– Pre-emergence or early post-emergence
• Uses– Control broadleaf weeds, grasses
• Soybeans, legumes• Rice
– Post-emergence on• Soybeans, wheat, barley, sugar beets
Cl or other sub-stituents required
Mode of Action
• Inhibit photosynthesis– Inhibit electron transport – Inhibit coupled photophosphorylation?– Some auxin-like action– Inhibit protoporphyrinogen oxidase
• Last common enzyme in synthesis of chlorophyll and hemoglobin
– (some diphenyl ethers may affect hemoglobin production , as shown by gray color of treated mice)
Acifluorfen
• Uses• Water solubility• Persistence
– Not very great• Toxicology
– LD50 po in rats• EPA: 1,300 mg/kg• UI Extension: 3,300 mg/kg
Oxyfluorfen• Water solubility: 0.1 ppm
– Bioaccumulation quite probable under normal use
– Herbicidal activity– 2-4 months (in medium-textured IL soil)
• Pre- and post-emergent herbicide– Broad range of crops
• Most uses cancelled in 1982
Oxyfluorfen toxicology
• Acute– LD50, po, in rats: 5,000 mg/kg
• Delayed effects– Probable mutagen– Probable carcinogen
• Contaminated with perchloroethylene
– Probable hepatotoxicant– Probable thyrotoxicant– Develomental toxicity data inadequate
Bifenox• Uses:• Paddy rice• Pre-emergent
– Corn, soybeans• Toxicity
– LD50, po, in rats:– UI Extension: 1,630– EPA: 6,400 mg/kg
• Delayed toxicities– Carcinogen??
• Ecotoxicology– Benign
Bifenox
Nitrofen
The 2nd group on the nitrophenyl ring of bifenox acts as a degradophore
Brief History of Nitrofen
• 1966: First registered in U.S.• 1971: Ambrose et al: Neonatal mortality at 100 ppm in
maternal diet• 1974: Kimbrough et al, Arch. Environ. Health: Neonatal
mortality confirmed• 1981: Costlow and Manson: Heart and lung defects
identified• 1981: Withdrawn from all U.S. uses
Toxicity of Nitrofen in Rats• Adult toxicity
– LD50 > 1 g/kg– Adverse effect at LOAEL: liver enlargement
• Fetal toxicity– NOAEL: < 0.1 mg/kg/day– Adverse effect at LOAEL: diaphragmatic
hernias– Other: heart, lung, kidney defects; cleft palate.
Reproductive Cycle
Human Development: Weeks 3 to 8
3 4 5
6 7 8
Protocol for 2-Generation AssayF0: parental animals
1st mating
F1A
Necropsy at weaning
2nd mating
F1B
Select F1 parental animals
F2BF2A
Necropsy at weaning
Necropsy F2B at weaning; including complete histopathology
Continue feeding chemical to each group at the appropriate dosing level throughout the study (progeny, too!)
Necropsy parents [F0 and F1] aftertheir 2nd litter is weaned.
Advantages of the 2-Generation Assay
• A single assay identifies:
– acute or cumulative toxicity leading to• male or female infertility, • pre- and post-natal mortality,• pre- and post-natal growth retardation,• functional deficits in offspring
– transplacental carcinogenesis– infertility– behavioral anomalies
The 2-Generation Assay: Disadvantages
• Cost– well over $500,000 per species
• but still cheaper than the alternatives…
• Labor-intensive– Necropsies of all parents– Necropsies of offspring of all litters– Histopathology of offspring from 2nd litters
• Identifies the existence of a problem, but not necessarily its nature
Advantages of the 2-Generation Assay
• A single assay identifies:
– acute or cumulative toxicity leading to• male or female infertility, • pre- and post-natal mortality,• pre- and post-natal growth retardation,• functional deficits in offspring
– transplacental carcinogenesis– infertility– behavioral anomalies
The 2-Generation Assay: Disadvantages
• Cost– well over $500,000 per species
• but still cheaper than the alternatives…
• Labor-intensive– Necropsies of all parents– Necropsies of offspring of all litters– Histopathology of offspring from 2nd litters
• Identifies the existence of a problem, but not necessarily its nature
Chemically induced birth defetcs
• Vary with– Chemical– Genotype
• Of dam and of embryo• Within and between species
– Developmental stage at time of exposure– Dose
• Either severity of defects or probability of defect increases with increasing dose
“Karnofsky’s Law”
• Any chemical, given at the right time, and at the right dose, to the right species will cause malformations
• The fact that a pesticide causes malformations in one species - especially at high doses - is not necessarily enough reason to ban it.
• In the case of nitrofen, malformations occurred in both rats and mice, but not in rabbits.
Developmental Toxicity is a Threshold Phenomenon
• For agents other than mutagens, there is a minimum dose that will not affect the embryo– because it is metabolized by the dam and does
not reach the embryo, and/or– it does not significantly perturb embryonic
development, and/or– compensatory mechanisms result in repair of
the damage.
Nitrofen
• Causes malformations– In both rats and mice
• Heart• Kidneys• Diaphragm• Eyes
– At a fraction of the adult LD50 • NOAEL in rats estimated at 0.03 mg/kg/day