Krueger and O'Brien (15) have shown that 
when mice and cockroaches are injected with 
30 mg. per kilogram of radioactive malathion, 
mala-oxon levels after 2 hours were approxi- 
mately 10 times as high in the cockroach as in 
the mouse. March et al. (18) and O'Brien (31) 
found that radioactive malathion was much 
more rapidly and extensively metabolized in 
the mouse than in the cockroach, Thus it ap- 
pears that the highly selective action to insects 
is the overall result of more rapid lethal syn- 
thesis in the insect and more rapid detoxica- 
tion in the mammal, 
Confirmation of this hypothesis has come 
about in a most interesting way through the 
work of Frawley and associates (8) on the 
possible synergistic or potentiating effects of 
simultaneous exposure of mammals to mala- 
thion and EPN (0-methyl 0-p-nitrophenyl 
phenylphosphorothioate). The individual and 
combined toxicities for these materials in a 
25:1 ratio are shown in table 6. It is evident 
that a marked degree of synergism was ob- 
served, In extensive biochemical investigations 
of this phenomenon, DuBois (7) found that the 
intravenous injection of rats with EPN at 1.5 
mg. per kilogram decreased, after 1 hour, the 
mala-oxon detoxifying capacity of the liver by 
84 percent and of the blood serum by 93 per- 
cent. This dosage of EPN also decreased the 
LDsg of malathion from 1,100 to 550 mg. per 
kilogram, Additionally it was shown (table 7) 
that relatively small amounts of dietary EPN 
would inhibit the enzymatic destruction of 
mala-oxon in rats. This suggested to DuBois 
that TOCP (tri-o-cresyl phosphate), which is 
well known as an aliesterase inhibitor, should 
also potentiate malathion. It was found that 
Table 6.--Potentiation of toxicity of 
malathion by EPN (8) 
[2250 mg. per kg. ] 

Insecticide Rat, oral 
Malathion (25) plus EPN (1) 
(Expected additive values). 

700 + 32.5 




16 
Table 7.--Effect of dietary EPN on 
mala-oxonase in rats (28) 








Inhibition mala-oxonase 
Percent 
39 
59 
81 
91 
95 
TOCP (i.p. LDsqg 2,500) when given to rats at 
110 mg. per kilogram decreased the LDs50 of 
malathion, given 24 hours later, from 1,100 
alone to 8,2 intraperitoneally. 
From these experiments it seems clear that 
the low toxicity of malathion to mammals is 
due to the high rate of carboxyesterase detoxi- 
cation of both malathion and its activation 
product mala-oxon by the mammalian liver, 
This principle of selectivity can undoubtedly 
be applied to many other molecules. O'Brien 
et al. (33) have produced a group of highly 
selective carboxyester derivatives of diethyl- 
Phosphoric acids, Acethion ((C9Hs50)9 
P(S)SCH9COOC9Hs5) had an i.p. LD59 to the 
mouse of 1,280 and a topical LD50 to the fly 
of 9.4 mg. per kilogram. Its selectivity was 
much greater than that of the more toxic 
P=O derivative acetoxon, demonstrating the 
importance of the delay factor (P=S oxidation) 
in providing an opportunity for enzymatic de- 
toxication in the mammal. 
From this discussion of selectivity of organ- 
ophosphorus insecticides, it may be concluded 
that careful molecular tailoring can produce 
O-P molecules with nearly any desired type of 
selectivity. The number of O-P compounds with 
insecticidal action is incredibly large. From the 
basic structure for toxic action (Schrader 37) 
