23 
Dr. Holmes questioned the effect the toxin might have on corneal or con- 
junctival cells in neonates bom vaginal ly of vrmen vaginal ly colonized by 
E. coli producing Shiga toxin. What might be the effect on the endocervix 
or endanetrium of women vaginal ly colonized by E^_ coli producing the toxin? 
What would be the effect on the male whose prostate might be colonized? 
Dr. Holmes questioned the language of the third recarurendation which 
specifies that the modified host-vector systen will not contain overlapping 
fragments which together would encompass the structural gene(s); he noted 
that JL_ coli K-12 host-vector systems may contain a chromosomal gene 
encoding Shiga toxin. 
Dr. Holmes said he was not persuaded that the preposed experiments require 
an Arms Control Impact Statement (ACIS) as argued by Mr. Rifkin in his 
May 15, 1984, letter. Dr. O'Brien’s proposed experiments are NIH funded 
and will be performed by civilian investigators associated with the Uniformed 
Services University of the Health Sciences (USUHS) medical school. He said 
he was not persuaded that the affiliation of the investigators with USUHS 
constitutes a reason per se for requiring an ACIS. 
Dr. Holmes suggested the issue as he saw it is not whether an ACIS is 
necessary for this particular experiment but whether any ACES might be 
needed for toxin related recombinant DNA experiments in general. 
Dr. Levine pointed out that when the Working Group on Tbxins was constituted 
in the spring of 1981 to evaluate the cloning of toxin genes, it was clear 
that experiments involving the cloning of the gene encoding botulinum toxin 
presented a real concern. Botulinum toxin is an exotoxinosis; i.e., the 
pure toxin if imbibed or ingested orally causes illness. Tetanus toxin also 
presents a real concern. Shiga toxin, on the other hand, is a very potent 
toxin when administered parenteral ly; however, there is no evidence qpidani- 
ologically or pathophysiologic ally that Shiga toxin by itself is capable of 
causing illness after ingestion. In 1981 in discussing the appropriate 
category for experiments involving cloning of the Shiga toxin gene, the 
Working Group on Toxins was divided. Seme individuals said these experiments 
should be in the same category as experiments involving the gene for tetanus 
toxin; this position was based on consideration of Shiga toxin's pharmaco- 
logical potency. Others felt Shiga toxin should be in a separate category 
on the basis of epidemiological evidence. As the hour was late, Shiga toxin 
was assigned to the same category as botulinum and tetanus toxin pending 
further information. Dr. Levine said most of the Working Group on Toxin 
members who participated in the May 11, 1984, meeting ware members of the 
working group which in the spring of 1981 drav up Appendix F to the NIH 
Guidelines. These individuals, thus, had the opportunity at the May 11, 
1984, meeting to review additional data concerning Shiga toxin and to offer 
recommendations. Dr. Levine pointed out that Swiss and West German cornu t- 
tees of experts have suggested experiments involving cloning of the Shiga 
toxin gene be permitted at no higher than P2 + EK1 containment. He said 
the recommendations of the RAC Working Group on Toxins in contrast represent 
a very conservative attitude towards the cloning of the Shiga toxin gene. 
He urged the RAC to accept the working group recommendations. 
[476] 
