A Physiologically Based Pharmacokinetic Model for 2,4-Toluenediamine Leached from Polyurethane Foam-Covered Breast Implants

Hoan-My Do Luu, Joseph C. Hutter and Harry F. Bushar
Environmental Health Perspectives
Vol. 106, No. 7 (Jul., 1998), pp. 393-400
DOI: 10.2307/3434066
Stable URL: http://www.jstor.org/stable/3434066
Page Count: 8
  • Download PDF
  • Cite this Item

You are not currently logged in.

Access your personal account or get JSTOR access through your library or other institution:


Log in to your personal account or through your institution.

A Physiologically Based Pharmacokinetic Model for 2,4-Toluenediamine Leached from Polyurethane Foam-Covered Breast Implants
We're having trouble loading this content. Download PDF instead.


Physiologically based pharmacokinetic (PBPK) modeling was used to assess the low-dose exposure of patients to the carcinogen 2,4-toluenediamine (2,4-TDA) released from the degradation of the polyester urethane foam (PU) used in Meme silicone breast implants. The tissues are represented as five compartments: liver, kidney, gastrointestinal tract, slowly perfused tissues (e.g., fat), and richly perfused tissues (e.g., muscle). The PBPK model was fitted to the plasma and urine concentrations of 2,4-TDA and its metabolite 4-AAT (4-N-acetyl-2-amino toluene) in rats given low doses of 2,4-TDA intravenously and subcutaneously. The rat model was extrapolated to simulate oral and implant routes in rats. After adjusting for human physiological parameters, the model was then used to predict the bioavailability of 2,4-TDA released from a typical 4.87-g polyester urethane foam implant found in a patient who weighed 58 kg with the Meme and had the breast implant for 10 years. A quantitative risk assessment for 2,4-TDA was performed and the polyester urethane foam did present an unreasonable risk to health for the patient.

Notes and References

This item contains 30 references.

References and Notes
  • 1
    cott Paper Co. Polymer Foam Modification. US patent 858,127.7 June 1957.
  • 2
    Picha GJ, Goldstein JA, Stohr E. Natural-Y Meme polyurethane versus smooth silicone: analysis of the soft-tissue interaction from 3 days to 1 year in the rat animal model. Plast Reconstr Surg85(6):903-916 (1990).
  • 3
    Smahel J. Tissue reactions to breast implants coated with polyurethane. Plast Reconstr Surg61(1):80-85 (1978).
  • 4
    Melmed EP. Polyurethane implants: a 6-year review of 416 patients. Plast Reconstr Surg82(2): 285-290 (1988).
  • 5
    Luu HMD, White KD. In-vitro detection of 2,4- and 2,6- TDA as degradation products of a polyesterurethane foam. Poly Degrad Stabil42:245-251 (1993).
  • 6
    Luu HMD, Biles J, White KD. Characterization of poly? esterurethane degradation Products. J Appl Bio Mater5:1-7 (1994).
  • 7
    Amin P, Willie J, Slah K, Kydonieus A. Analysis of the extractive and hydrolytic behavior of microthane poly(ester-urethane) foam by high pressure liquid chro? matography. J Biomed Mater Res27:655-666 (1993).
  • 8
    Batich C, Williams J, King R. Toxic hydrolysis product from a biodegradable foam implant. J Biomed Mater Res23:311-319 (1989).
  • 9
    Benoit MF. Degradation of polyurethane foams used in the Meme breast implant. J Biomed Mater Res 27:1341-1348(1993).
  • 10
    Glinsukon T, Benjamin T, Grantham PH, Weisburger EK, Roller PP. Enzymic N-Acetylation of 2,4-toluenediamine by liver cytosols from various species. Xenobiotica 5(8):475-483(1975).
  • 11
    Grantham PH, Mohan L, Benjamin T, Roller PP, Miller JR, Weisburger EK. Comparison of the metabolism of 2,4-toluenediamine in rats and mice. J Envron Pathol Toxicol3:149-166 (1979).
  • 12
    Waring RH, Pheasant AE. Some phenolic metabolites of 2,4-toluenediamine in the rabbit, rat, and guinea pig. Xenobiotica6(4):257-262 (1976).
  • 13
    Weisburger EK, Russfield AB, Homburger F, Weisburger JH, Boger E, Van Dongen CG, Chu KC. Testing of twenty-one environmental aromatic amines or derivatives for long term toxicity or car? cinogenicity. J Environ Path Toxicol2:325-356 (1978).
  • 14
    Ito N, Hiasa Y, Konishi Y, Marugami M. The develop- ment of carcinoma in liver of rats treated with M- toluylenediamine and the synergistic and antagonistic effects with other chemicals. Cancer Res29(5): 1137-1145(1969).
  • 15
    National Cancer Institute.Bioassay of 2,4- Diaminotoluene for Possible Carcinogenicity. NCI Technical Report Series No.162. Bethesda, MD:National Cancer Institute, 1979.
  • 16
    Timchalk C, Smith FA, Bartels MJ. Route-dependent comparative metabolism of [14C]toluene 2,4-diiso- cyanate and [14C]toluene 2,4-diamine in Fisher 344 rats. Toxicol Appl Pharmacol124:181-190 (1994).
  • 17
    Kadlubar FF, Hammons GJ. The role of cytochrome P-450 in the metabolism of chemical carcinogens. In: Mammalian Cytochromes P-450, vol II (Guengerich FP, ed). Boca Raton, FLCRC Press, 1987;81-130.
  • 18
    IARC2,4-Diaminotoluene. In: IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Vol 16: Some Aromatic Amines and Related Compounds?Hair Dyes, Colouring Agents and Miscellaneous Industrial Chemicals. Lyon:lntemational Agency for Research on Cancer, 1978;83-95.
  • 19
    WHODiaminotoluenes. Environmental Health Criteria No 74. Geneva:World Health Organization, 1987.
  • 20
    Chan SC, Birdsell DC, Gradee CY. Detection of toluene- diamines in the urine of a patient with polyurethane covered breast implants. Clin Chem37(5):756-758 (1991).
  • 21
    Chan SC, Birdsell DC, Gradee CY. Urinary excretion of free toluenediamines in a patient with polyurethane- covered breast implants. Clin Chem37(12):2143-2145 (1991).
  • 22
    Sepai 0, Henschler D, Czech S, Eckert P, Sabbioni G. Exposure to toluenediamines from polyurethane-cov- ered breast implants. Toxicol Lett77:371-378 (1995).
  • 23
    Food and Drug Administration. CDRH Toxicology Risk Assessment Committee Report on Polyester Polyurethane Foam Covering of Silicone Gel Filled Breast Implants. FDA Memorandum, 22 July 1991.
  • 24
    Expert Panel of the Canadian Medical Association. Safety of polyurethane-covered breast implants. Can Med Assoc J145:1125-1128(1991).
  • 25
    Krishnan K, Anderson ME. Physiologically based pharmacokinetic modeling in toxicology. In: Principles and Methods of Toxicology (Hayes WA, ed). 3rd ed. New York: Raven Press, 1994;149-188.
  • 26
    Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. Physiological parameter values for physi? ologically based pharmacokinetic models. Toxicol Ind Health13:407-484(1997).
  • 27
    Ramsey JR, Anderson ME. A physiologically based description ofthe inhalation pharmacokinetics of styrene in rats and humans. Toxicol Appl Pharmacol 73:159-175(1984).
  • 28
    Anderson ME, Clewell HJ, Gargas ML, Smith FA, Reitz RH. Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. Toxicol Appl Pharmacol87:185-205 (1987).
  • 29
    FDADiscretionary Postmarket Surveillance Protocol for the Meme and Replicon Polyester/ Polyurethane- covered Mammary Products. DPS 920001. Rockville, MD:Food and Drug Administration, 1992.
  • 30
    Chasseaud LF.Role of toxicokinetics in toxicity testing. In: Drug Toxicokinetics (Welling P, Iglesia FA, eds, Drug and Chemical Toxicology, Vol 9. New York:Marcel Dekker, Inc. 1993;105-142.