Metabolic studies in both humans and other mammals

Metabolic studies in both humans and other mammals show that bis-phenol A is rapidly eliminated
from the body (< 24 h). Following uptake from the GI tract, the compound is conjugated (Phase II/tra
pp in g) in the liver with glucuronic acid (a sugar derivative). The water-soluble glucuronide is ex cret
ed in the urine. Metabolism follows a slightly different pathway in the rat, in which the glucuronide
adduct is transported to the bile and re-enters the digestive system. Enterohepatic recycling results in
a longer whole-body half-life and the higher proportion of excretion in the feces, compared with the
human.
There is a need for epidemiological and dose-response studies to assess properly the human health
implications of exposure to bis-phenol A. The Canadian government’s response in 2008 was based
on the so-called “precautionary principle” which states that new substances should not be introduced
into the marketplace until they have been proved to be safe.
As previously noted, it is never possible to prove a negative – that no toxic outcomes will result from
exposure to any substance. Instead, one can only make statements along the lines of “the likelihood
of an adverse condition will be no more than (say) one in 10 6 .” This question will be addressed more
fully in the section of the course on Regulatory Toxicology.

1-49
P
N
CO
2
H
H
OH
OH
O
CH
2
O CO
2
H
OH
P
i
O
CO
2
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OH
CO
2
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1.6.8
HERBICIDE
s
In case these notes leave the impression that toxicology is exclusively a mammalian concern, we will
finish this section by examining the mechanism of action of a group of herbicides. Many herbicides
target aspects of the photosynthetic apparatus, and therefore have low animal toxicity.
Glyphosate
Glyphosate, N-(phosphonylmethyl)glycine (marketed as the isopropylammonium salt by Monsanto
under the name Roundup) is a broad spectrum herbicide that kills plants following foliar uptake.
Glyphosate has very low mammalian toxicity (LD
50
> 1 g/kg in all species tested) and only slight
toxicity to aquatic animals (LC
50
> 100 mg/L in all species tested except trout (11 mg/L). It also has
zero to low potency in terms of carcinogenicity, neurotoxicty and teratogenicity in mammals, making it
non-hazardous to (animal) non-target organisms. In soil, glyphosate is made biologically unavailable
by binding to clay, and is inactivated by microorganisms. In most soils this occurs within days,
accounting for the attractive feature of glyphosate to farmers: weeds can be destroyed and a crop
plant ed almost immediately afterwards.
Glyphosate is absorbed by foliar uptake and rapidly distributed systemically. Its mechanism of action
is well understood; it inhibits the enzyme 5-enolpyruvyl shikimic acid-3-phosphate synthase. This
enzyme catalyzes a critical step in the synthesis of aromatic aminoacids (phenylalanine, tyrosine,
tryptophan). When the enzyme is inhibited, these cannot form; protein synthesis ceases as the plan
ts stores of these aminoacids are used up, and the plant dies (although this process can be reversed
if the aromatic aminoacids are supplied exogenously). This mechanism of action explains why the
die-off of the plants occurs over a period of 7-14 days.