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This article reviews the mechanistic basis of the tissue residue approach for toxicity assessment (TRA). The tissue residue approach implies that whole-body or organ concentrations (residues) are a better dose metric for describing toxicity to aquatic organisms than is the aqueous concentration typically used in the external medium. Although the benefit of internal concentrations as dose metrics in ecotoxicology has long been recognized, the application of the tissue residue approach remains limited. The main factor responsible for this is the difficulty of measuring internal concentrations. We propose that environmental toxicology can advance if mechanistic considerations are implemented and toxicokinetics and toxicodynamics are explicitly addressed. The variability in ecotoxicological outcomes and species sensitivity is due in part to differences in toxicokinetics, which consist of several processes, including absorption, distribution, metabolism, and excretion (ADME), that influence internal concentrations. Using internal concentrations or tissue residues as the dose metric substantially reduces the variability in toxicity metrics among species and individuals exposed under varying conditions. Total internal concentrations are useful as dose metrics only if they represent a surrogate of the biologically effective dose, the concentration or dose at the target site. If there is no direct proportionality, we advise the implementation of comprehensive toxicokinetic models that include deriving the target dose. Depending on the mechanism of toxicity, the concentration at the target site may or may not be a sufficient descriptor of toxicity. The steady-state concentration of a baseline toxicant associated with the biological membrane is a good descriptor of the toxicodynamics of baseline toxicity. When assessing specific-acting and reactive mechanisms, additional parameters (e.g., reaction rate with the target site and regeneration of the target site) are needed for characterization. For specifically acting compounds, intrinsic potency depends on 1) affinity for, and 2) type of interaction with, a receptor or a target enzyme. These 2 parameters determine the selectivity for the toxic mechanism and the sensitivity, respectively. Implementation of mechanistic information in toxicokinetic-toxicodynamic (TK-TD) models may help explain timedelayed effects, toxicity after pulsed or fluctuating exposure, carryover toxicity after sequential pulses, and mixture toxicity. We believe that this mechanistic understanding of tissue residue toxicity will lead to improved environmental risk assessment. Integr Environ Assess Manag 2011;7:28-49. ß 2010 SETAC

A damage assessment model (DAM) was developed to describe and predict the toxicity time course for PAH in Hyalella azteca. The DAM assumes that death occurs when the cumulative damage reaches a critical point and was described by a combination of both first-order toxicokinetic and toxicodynamic models. In aqueous exposures, body residues increase in proportion to the water concentration. Damage is assumed to accumulate in proportion to the accumulated residue and damage recovery in proportion to the cumulative damage when damage is reversible. As a result, the toxicity time course, LC50(t), is determined by both a damage recovery rate and an elimination rate. The constant critical body residue (CBR) and the critical area under the curve (CAUC) models can be derived as two extreme cases from the DAM, and all three models were reanalyzed using a hazard modeling approach. As a result, the critical cumulative damage (D(L)) is the determinant of the concentration-time response relationship and not simply the CBR or the CAUC. Finally, from the DAM, two parameters, a damage recovery rate constant kr and the killing rate kt, were estimated and found to be relatively constant for selected PAH.

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The relationship between toxicokinetics and time-dependent PAH toxicity to Hyalella azteca was examined to test the constant critical body residue (CBR) model. A constant CBR model is based on the assumption that the body residue for 50% mortality is constant for each PAH across exposure times. With a constant CBR, kinetic parameters determined through kinetic experiments would be similar to those estimated from time series toxicity data. Time-dependent toxicity was investigated using three types of data: time series LCW data, LT50(c), and CBR values measured at multiple exposure times for live and dead animals. Kinetic parameters were measured independently. The constant CBR model did not predict the PAH toxicity time course for H. azteca. Since a first-order kinetic model predicted the bioaccumulation of the parent PAH except for naphthalene, this result is not due to a failure to predict the internal dose (body residue). The influence of metabolites on toxicity was negligible except for naphthalene. The LC50 values at multiple exposure times decreased to an incipient lethal concentration after H. azteca reached steady state. Measured CBR values also decreased with increasing exposure time. Thus, the time course of PAH toxicity is determined not only by the bioconcentration kinetics but also by the cumulative toxicity with increasing exposure time. Therefore, time-to-death or hazard models must be developed as a complement to toxicokinetic models to describe and predict the toxicity time course.

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We present a related family of authentication and digital signature protocols based on symmetric cryptographic primitives which perform substantially better than previous constructions. Previously, one-time digital signatures based on hash functions involved hundreds of hash function computations for each signature; we show that given online access to a timestamping service, we can sign messages using only two computations of a hash function. Previously, techniques to sign infinite streams involved one such one-time signature for each message block; we show that in many realistic scenarios a small number of hash function computations is sufficient. Previously, the Diffie Hellman protocol enabled two principals to create a confidentiality key from scratch: we provide an equivalent protocol for integrity, which enables two people who do not share a secret to set up a securely serialised channel into which attackers cannot subsequently intrude. In addition to being of potential use in real applications, our constructions also raise interesting questions about the definition of a digital signature, and the relationship between integrity and authenticity.

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