1. Diphenyl Ethers And Developmental Toxicity
HERBICIDES:
Diphenyl Ethers
And
Developmental Toxicity

2. 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

3. 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)

4. Acifluorfen Not very great LD50 po in rats Uses Water solubility
Persistence
Not very great
Toxicology
LD50 po in rats
EPA: 1,300 mg/kg
UI Extension: 3,300 mg/kg

5. Oxyfluorfen Bioaccumulation quite probable under normal use
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

6. 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

7. Bifenox Uses: Paddy rice Pre-emergent Toxicity Delayed toxicities
Corn, soybeans
Toxicity
LD50, po, in rats:
UI Extension: 1,630
EPA: 6,400 mg/kg
Delayed toxicities
Carcinogen??
Ecotoxicology
Benign

8. Bifenox
The 2nd group on the nitrophenyl ring of bifenox acts as a degradophore
Nitrofen

9. 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1981: Withdrawn from all U.S. uses

10. 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.

11. Reproductive Cycle

12. Human Development: Weeks 3 to 85 3 4 6 7 8

13. Protocol for 2-Generation Assay
F0: parental animals
2nd mating
F1B
1st mating
Necropsy parents [F0 and F1] aftertheir 2nd litter is weaned.
Select F1 parental animals
Necropsy at weaning
F1A
Necropsy F2B at weaning; including complete histopathology
Necropsy at weaning
F2B
F2A
Continue feeding chemical to each group at the appropriate dosing level throughout the study (progeny, too!)

14. 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

15. 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

16. 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

17. 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

18. 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

19. Thalidomide-induced malformations occur
days after the last menstrual period

20. “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.

21. 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.

22. 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