Studies on the non-pathogenicity of Chryseobacterium proteolyticum and on the safety of the enzyme: protein-glutaminase.

Protein-glutaminase (PG) is a protein-deamidating enzyme produced from the microorganism Chryseobacterium proteolyticum strain 9670. Food safety studies were conducted on both the enzyme and the production organism. The strain was evaluated for pathogenicity and toxigenicity by intravenous and oral inoculation studies in Slc:ICR male SPF mice. The results demonstrate that the tested C. proteolyticum strain is of very low pathogenicity comparable to known food source bacterial strains and is very unlikely to demonstrate any pathogenicity in animals or humans. The level of endotoxin is very low and typical of the endotoxin levels in drinking water and teas. A 90-day study of PG, conducted in Sprague-Dawley rats, showed no adverse effects due to the enzyme up to dose levels of 2500 mg/kg-bw/day (NOAEL). Details of the study are presented, including, organ and body weights, histological findings, and blood and urine chemistry. Additionally, bacterial reverse mutation test (Ames test) and chromosomal aberration test using mammalian established cell line were conducted, resulting in the absence of mutagenicity in PG.

Differential sensitivity of children and adults to chemical toxicity. I. Biological basis.

Children, particularly neonates, can be biologically more sensitive to the same toxicant exposure on a body weight basis than adults. Current understanding of the rates of maturation of metabolic capability and evidence from case examples on pharmaceuticals, drugs of abuse, environmental contaminants, and dietary and endogenous agents indicate that human infants up to approximately 6 months of age are typically--but not always--more sensitive to chemical toxicity than adults. For most chemicals, the immaturity of infant biotransformation, elimination, and other physiologic systems usually produces higher blood levels for longer periods. There is metabolic capacity for most tested substances in the newborn, although it is quite low and immature for some chemicals. For some chemicals, unique metabolic pathways not available in the adult human can also be utilized by the newborn. The newborn's metabolic capacity rapidly matures and, by about 6 months of age, children are usually not more sensitive to chemical toxicity than adults. By then, most metabolic systems are reasonably mature, becoming almost completely capable by 1 year of age. In many cases children are less sensitive than adults. Whether children are at greater risk from chemical exposures is another question. Risk depends on both inherent sensitivity and exposure conditions. If chemical exposure levels remain below those capable of overwhelming a child's metabolic detoxification systems and producing toxicity, children will be at no greater risk than are adults. Children of all ages are still developing so even if they are exposed to chemicals at levels below those of adults, they may be at greater risk than adults. However, as long as those exposure levels are still below those required to produce toxicity, children will not be at greater risk.

Differential sensitivity of children and adults to chemical toxicity. II. Risk and regulation.

Animals can be useful predictors of chemical hazards to humans. Growth and development are compressed into a shorter period in animals, which makes interpretation of animal testing inherently more difficult. However, similar events occur in both humans and laboratory animals and testing that covers the full period of animal development can reasonably be considered an appropriate surrogate for human development. Some have proposed an additional 10-fold factor for the extra protection of children when estimating safe exposures. Use of such an additional factor, as required by the Food Quality Protection Act (FQPA), is meant to address the same issues covered by the EPA's database uncertainty factor, UF(D), and additional issues related to exposure uncertainty. Thus, when UF(D) has already been deployed, the EPA modifies its use of the FQPA factor. Based on our analysis, we agree with the EPA. Drawing conclusions about the adequacy of UF(H), the uncertainty factor used to account for intrahuman variability, in terms of its ability to protect children on the basis of the modest data available is challenging. However, virtually all studies available suggest that a high percentage of the population, including children, is protected by using a 10-fold uncertainty factor for human variability or by using a 3.16-fold factor each for toxicokinetic and toxicodynamic variability. Based on specific comparisons for newborns, infants, children, adults, and those with severe disease, the population protected is between 60 and 100%, with the studies in larger populations that include sensitive individuals suggesting that the value is closer to 100%.