MUTAGENS OF POTENTIAL SIGNIFICANCE 211 



who are never disturbed by either caffeine or placebo under these 

 same conditions. 



Our initial hypothesis was that the difference between reactors and 

 nonreactors might well be in the absorption of caffeine from the 

 gastrointestinal tract into the blood stream. This would not have been 

 too surprising and would have been convenient, but it turned out to be 

 entirely untrue. There was absolutely no difference in the rate of 

 absorption or the blood levels achieved in these two groups. Presum- 

 ably, the difference is referable to some properties of the brain itself or 

 the i)cnetration of caffeine to sites of action in the brain. Whatever the 

 reason may be, there are important differences in the way people react 

 to caffeine and in the extent of their desire for the effects of caffeine. 

 These factors play a role in determining whether a person becomes a 

 heavy coffee drinker. The reason why I stress this is that it makes it 

 a little easier to consider what Dr. Neel rejected out of hand before, 

 namely, the possibility that within a human population, one could 

 define caffeine-exposed and caffeine-nonexposed individuals reliably 

 enough to permit a comparative investigation of the incidence of gen- 

 etic disease in their progeny. 



As to the access of caffeine to the gonads, there is no direct 

 evidence about this in man. As I said before, the presumptive evidence 

 would be that caffeine has access to the gonads and germ cells, just 

 as it has access to all other cells in the body. One must ask also 

 about access to the fetus and its germ cells during the sensitive 

 early period we postulated this morning. I know of only one experi- 

 ment to determine whether caffeine passes in to the fetus from the 

 mother, and that is an old one, done in 1934 in the dog, with very high 

 caffeine levels and late in pregnancy. 



In that experiment (22), there was complete passage of caffeine 

 from maternal blood to fetal blood, and equal caffeine levels in the 

 maternal and fetal livers. This is not too decisive, however, because 

 there is a feeling among people who have studied such problems, and 

 there are some experimental data to indicate, that the placenta passes 

 substances more easily later in pregnancy than earlier (60) . There 

 have been studies, for example (24) , on the passage of isotopic sodium 

 from maternal to fetal circulation in the human, in cases where 

 pregnancy had to be terminated for one reason or another. These 

 show ciuite clearly that the passage rate increases with time during 

 gestation. It therefore must be left open whether in the early period 

 of gestation, when mutagenic substances might be especially hazardous, 

 they may also be less able to cross the placenta into the fetus. 



