April 2, 2002

Ms. Britt Erickson
Environmental Science & Technology
Washington, DC
Via e-mail: est@acs.org

Dear Ms. Erickson:

As a follow-up on our conversation, the following is a summary of our comments on the paper by K. Guenther et al. ("Endocrine Disrupting Nonylphenols Are Ubiquitous in Food," Environmental Science & Technology 36, 2002):

• The nonylphenol (NP) levels reported in food are not only very low, they are reassuringly low because they are lower than those predicted by regulatory agencies. The fact that the levels are lower than predicted safe levels supports the approval of nonylphenol derivatives for continued use.

• The article speculates that one source of the NP may be from the use of NP derivatives in packaging. This is not new news and once again is consistent with the regulatory approvals for these products.

  As we noted, there are hundreds of chemicals approved for use in such things as packaging under the assumption that trace levels can find their way to food (i.e., indirect food additives). If one uses sophisticated methods to analyze for these substances in food (which is rarely done), it is likely, and anticipated by the regulatory agencies, that low levels will be found.

• The article also speculates that the source of the NP may come from NPE used in pesticides. This is also a regulated use and the low levels reported are consistent with the regulatory approvals for these products.

• The EU risk assessment and a separate German assessment (Bolt et al., 2000) calculated maximum (worst-case) daily dietary exposure to NP and concluded that the predicted levels of exposure (2µg/kg body weight per day) did not represent a health risk. In fact, the levels of exposure measured by Guenther et al. (0.28 µg/kg/d for infants fed soy-based formula; 0.1 µg/kg/d for adults) are seven times less than the predicted safe values, confirming the safety of current uses of NP derivatives.

In general, the article should be viewed as positive since it documents that measured levels of NP in food are less than worst-case predictions, which are considered not to pose a risk to human health. Further details on these safety calculations are provided in the attachment.

I would also like to further draw your attention to a few inaccurate statements in the Guenther et al. paper:

"These compounds are known to be persistent, toxic..." "During the different steps of the sewage treatment process...leading to the formation of biorefractory metabolites (5,6). Especially the formed NPs are persistent and toxic, and after release in the aquatic environment they accumulate in aquatic organisms (7-9)"

These statements are in direct conflict with the recent published results of the behavior of NP and its metabolites in wastewater treatment facilities (Bennie and Webber, 2000). As we discussed, some of the confusion results from the loose use of terms. For example, individuals may have different definitions for the use of the term "persistence," which is why various regulatory and international bodies have developed criteria for such terms. I have attached a table, which identifies the classifications used by some of the more prominent organizations. As you will readily note, NP is not considered persistent under the classification schemes devised by the US EPA, Environment Canada and the United Nations. Also, recent publications indicate that NPEs and NP are inherently biodegradable (Staples et al., 1999 and Staples et al., 2001) and have only a moderate potential to bioaccumulate in wildlife (Staples et al., 1998, Coldham et al., 1998 and others) or in humans (Muller et al., 1998). Based on these findings, NP and its derivatives should not be considered persistent or biorefractory. We appreciate Environmental Science & Technology's effort to correct these inaccurate characterizations.

Please let me know if I can provide you with additional information. Once again, I would like to express our appreciation for the opportunity to comment on the Guenther et al. (2002) paper.

Sincerely,

Robert J. Fensterheim
Executive Director

---

References

Bennie, D.T. and Webber, M. 2000. Fate of alkylphenolics in sludge-amended soil. 21st Annual Meeting of the Society of Environmental Toxicology and Chemistry, Nashville, TN. p.193.

Staples, C.A., Williams, J.B., Blessing, R.L. and Varineau, P.T. 1999. Measuring the biodegradability of nonylphenol ether carboxylates, octylphenol ether carboxylates and nonylphenol. Chemosphere 38:2029-2039.

Staples, C.A., Naylor, C.G., Williams, J.B. and Gledhill, W.E. 2001. Ultimate biodegradation of alkylphenol ethoxylate surfactants and their biodegradation intermediates. Environ Toxicol Chem 20:2450-2455.

Staples, C.A., Weeks, J., Hail, J.F. and Naylor, C.G. 1998. Evaluation of aquatic toxicity and bioaccumulation of C8-and C9-alkylphenol ethoxylates. Environ Toxicol Chem 17:2470-2480.

Coldham, N.G., Sivapathasundaram, S., Dave, M., Ashfield, L.A., Pottinger, T.G., Goodhall, C. and Sauer, M.J. 1998. Biotransformation, tissue distribution and persistence of 4-nonylphenol residues in juvenile rainbow trout (Oncorhynchus mykiss). Drug metabolism and Disposition 26:347-354.

Muller, S., Schmid, P. and Schlatter, C. 1998. Pharmacokinetic behavior of 4-nonylphenol in humans. Environ Toxicol Pharmacology 5:257-265.

---

Details for Food Safety Assessment

The following provides detailed technical comments for consideration in assessing the significance of the results from the publication, K. Guenther et al. "Endocrine Disrupting Nonylphenols Are Ubiquitous in Food," Environmental Science & Technology 36, 2002:

1. A safety assessment for nonylphenol (NP) in foods, conducted in Germany by Dr. Bolt used a higher (worst-case) estimate of NP levels in foods than those reported by Guenther et al. Even with these higher levels, Dr. Bolt concluded "the absence of a practical risk to human health:" ¹

   1. A "hygiene-based margin of safety (HBMOS)" assessment was conducted by comparing exposure scenarios and potency data for industrial chemicals and naturally occurring dietary compounds with estrogenic activity. Based on estimates by the Deutsche Forschungsgemeinschaft, phytoestrogen² intake is about 1 mg/kg/d.³ Under worst-case assumptions, dietary exposure to NP was estimated at 2 µg/kg/d. Consequently, dietary levels of NP are 500-times lower than phytoestrogen levels. It is significant to note that phytoestrogen consumption in Germany is one of the lowest in the industrialized world and is significantly less than, for example, Asian cultures. Consequently, comparison of NP dietary exposures in other cultures would show larger margins of safety compared to the natural phytoestrogens in the diet.

   2. On the basis of comparative data from uterotrophic assays in rats, with three consecutive days of oral application, and other available data, the authors conclude that NP has either 2 or 4-times the potency of daidzein, the primary phytoestrogen consumed in Germany.⁴

   3. Based on a margin of activity basis, worst-case dietary levels of NP are either 125 or 250-times less than the phytoestrogens in the typical Western diet. The results of the HBMOS assessment thus indicate "no risk to human health under the present exposure conditions."

2. Based on available toxicological studies, the levels of NP reported in food in Germany pose no discernable risk to human health.

   1. Guenther et al. (2002) estimated that the daily intake of NP for infants in Germany ranges from 0.2 to 1.4 µg/day. Dividing by a common estimate for infant body weight (first year of life) of 5 kg (11 lb) gives an estimated dietary intake of 0.04 to 0.28 µg/kg/day. Excluding renal tubular effects,⁵ this exposure range is approximately 40,000 to 300,000 fold lower than the lowest no observed adverse effect level in any animal study, (13,500 µg/kg/day,⁶) which was reported from the US National Toxicology Program's three generation reproduction study on NP.⁷ Note that the multigeneration study includes continuous exposure of the laboratory animals so that all life stages are covered, including those analogous to the first year of life of a human infant.

   2. The daily intake of NP for adults was estimated by Guenther et al. to be 7.5 µg/day. Dividing by 70 kg (154 lb), which is considered a standard estimate for an adult body weight (average of men's and women's body weights) gives an estimated daily intake for adults of 0.107 µg/kg/d. This daily intake is 100,000 fold lower than the 13,500 ug/kg/day5 NOAEL noted above.

---

1. H.M. Bolt et al. 2001 Comparative Assessment of Endocrine Modulators with Estrogenic Activity: I. Definition of a Hygiene-based Margin of Safety (HBMOS) for Xeno-estrogens against the Background of European Developments. Archives of Toxicology 74:649-662.
2. Primarily the isoflavones daidzein and genistein and plant lignans, with the highest quantities found in soybeans and flaxseed, respectively. (Bolt et al., 2001)
3. European Union, Risk Assessment of 4-Nonylphenol (Branched) and Nonylphenol, Human Health Effects, European Chemicals Bureau, Ispra, Italy. 1999.
4. Genistein, which tends to be more estrogenically active than daidzein, is more frequently consumed in other cultures.
5. Chapin et al. (1999) reported that "the renal changes occurred consistently at all dose levels," a questionable finding, especially since these effects were not observed at the 200 or 650 ppm NP dose of a 90-day subchronic study on rats that used the same dosing scheme as the multigeneration study (H.C. Cunny et al. 1997 Subchronic Toxicity (90-Day) Study with para-Nonylphenol in Rats. Regulatory Toxicology and Pharmacology 26:172-178).
6. Median daily dose range 8,000-19,000 µg/kg/day, lactational dose range, 15,000-36,000 µg/kg/d at a dose of 200 ppm NP in the diet, see Table 2 of R.E. Chapin et al. 1999 The Effects of 4-Nonylphenol in Rats: A Multigeneration Reproduction Study. Toxicological Sciences 52:80-91.
7. Chapin et al. 1999.

 

Site Map   ·   Feedback/Contact Us   ·   Members Only