Evaluating the impact of anatomical and physiological variability on human equivalent doses using PBPK models.

Addressing human anatomical and physiological variability is a crucial component of human health risk assessment of chemicals. Experts have recommended probabilistic chemical risk assessment paradigms in which distributional adjustment factors are used to account for various sources of uncertainty and variability, including variability in the pharmacokinetic behavior of a given substance in different humans. In practice, convenient assumptions about the distribution forms of adjustment factors and human equivalent doses (HEDs) are often used. Parameters such as tissue volumes and blood flows are likewise often assumed to be lognormally or normally distributed without evaluating empirical data for consistency with these forms. In this work, we performed dosimetric extrapolations using physiologically based pharmacokinetic (PBPK) models for dichloromethane (DCM) and chloroform that incorporate uncertainty and variability to determine if the HEDs associated with such extrapolations are approximately lognormal and how they depend on the underlying distribution shapes chosen to represent model parameters. We accounted for uncertainty and variability in PBPK model parameters by randomly drawing their values from a variety of distribution types. We then performed reverse dosimetry to calculate HEDs based on animal points of departure (PODs) for each set of sampled parameters. Corresponding samples of HEDs were tested to determine the impact of input parameter distributions on their central tendencies, extreme percentiles, and degree of conformance to lognormality. This work demonstrates that the measurable attributes of human variability should be considered more carefully and that generalized assumptions about parameter distribution shapes may lead to inaccurate estimates of extreme percentiles of HEDs.

Flood Risk to Hospitals on the United States Atlantic and Gulf Coasts From Hurricanes and Sea Level Rise.

Hurricanes have caused major healthcare system disruptions. No systematic assessment of hurricane risk to United States hospital-based healthcare delivery has been performed. Here, we show that 25 of 78 metropolitan statistical areas (MSAs) on the United States Atlantic and Gulf Coasts have half or more of their hospitals at risk of flooding from relatively weak hurricanes. 0.82 m of sea level rise expected within this century from climate change increases the odds of hospital flooding 22%. Furthermore, in 18 MSAs at least half of the roads within 1.6 km of hospitals were at risk of flooding from a category 2 storm. These findings identify previously undescribed risks to hospital-based care delivery in Atlantic and Gulf Coast communities. They suggest that lower intensity hurricanes can have outsized impacts on healthcare access, particularly in places where per capita bed availability is low.

The orienting response in schizophrenia and mania.

We examined skin conductance (SCR) and finger pulse amplitude response (PULSE) in 53 schizophrenic, 30 manic, and 28 control subjects to provide information on orienting response (OR) dysfunction in severe psychiatric disorders. SCR and PULSE to neutral and task-relevant tones were measured in acutely ill inpatients and normal control subjects on two occasions separated by a 3-week interval. There were no significant group differences in proportions of SCR and PULSE non-responders to neutral tones. PULSE frequency to task-relevant tones in both the schizophrenic and manic patients was lower than that for the control subjects in both OR sessions, but did not differ significantly between patient groups. Although PULSE frequency was inversely related to neuroleptic dose in the schizophrenia sample, reanalysis of unmedicated patients did not change our results. OR frequency to task-relevant but not to neutral tones exhibited test-retest reliability. Certain aspects of OR dysfunction may overlap in schizophrenia and bipolar disorder. Our failure to demonstrate excessive OR non-responding to neutral tones in schizophrenia patients is inconsistent with many previous studies but may be due to a high proportion of OR non-responders among the control subjects.

Differing patterns of electrodermal and finger pulse responsivity in schizophrenia and depression.

Non-response of the autonomic orienting response (OR), as indexed jointly by deficient skin conductance (SCR) and finger pulse amplitude responding (FPAR), has been shown to occur with excessive frequency in the schizophrenic population. The present study is an attempt to replicate earlier evidence that SCR-OR and FPAR-OR, when measured in concert, could distinguish schizophrenic from depressed patients (Bernstein et al. 1988). This issue is critical of the question of diagnostic specificity of OR non-responding, since reduced SCR has been found repeatedly in depression as well as in schizophrenia. We examined SCR and FPAR concurrently in 69 schizophrenic, 45 depressed, and 67 normal subjects. SCR non-responding was more frequent in both schizophrenics and depressives than in normal controls, while only the schizophrenics displayed excessive FPAR non-responding. Moreover, among SCR non-responders, concordant OR non-responding--defined as non-responding indexed simultaneously in both the SCR and FPAR components--was most common in the schizophrenic sample. These findings support our previous conclusion that OR non-responding in depression, may have distinct peripheral origins. Our results also suggest that measuring multiple biochemically distinct components of the OR may be more sound methodologically than obtaining a single channel recording.

The relationship of the skin conductance and finger pulse amplitude components of the orienting response to season of birth in schizophrenia and depression.

Schizophrenia is said to be associated with a modest excess of winter births. We examined relations of season of birth (SOB) to the skin conductance response (SCR) and finger pulse amplitude response (FPAR) components of the orienting response (OR) in 83 schizophrenic patients, 59 depressed patients, and 81 normal controls. SCR-OR nonresponding was more prevalent among depressed patients regardless of SOB, whereas only winter-born schizophrenics showed significantly more frequent electrodermal nonresponding than controls. However, this latter relation was not confirmed with log linear analysis. No other relations of SOB to SCR-OR or FPAR-OR nonresponding were significant. Our data do not support the view that nonresponding in the SCR or FPAR components of the OR is associated with winter birth either in schizophrenia or depression.

Artificial neural network classification of Drosophila courtship song mutants.

Courtship songs produced by Drosophila males--wild-type, plus the cacophony and dissonance behavioral mutants--were examined with the aid of newly developed strategies for adaptive acoustic analysis and classification. This system used several techniques involving artificial neural networks (a.k.a. parallel distributed processing), including learned vector quantization of signals and non-linear adaption (back-propagation) of data analysis. "Pulse" song from several individual wild-type and mutant males were first vector-quantized according to their frequency spectra. The accumulated quantized data of this kind, for a given song, were then used to "teach" or adapt a multiple-layered feedforward artificial neural network, which classified that song according to its original genotype. Results are presented on the performance of the final adapted system when faced with novel test data and on acoustic features the system decides upon for predicting the song-mutant genotype in question. The potential applications and extensions of this new system are discussed, including how it could be used to screen for courtship mutants, search novel behavior patterns or cause-and-effect relationships associated with reproduction, compress these kinds of data for digital storage, and analyze Drosophila behavior beyond the case of courtship song.

The effects of prolonged stimulus repetition with repeated switching of target status on the orienting response in schizophrenia and depression.

Schizophrenic patients are frequently orienting nonresponders to innocuous stimuli, become responsive to significant target signals, and become hyporesponsive again on prolonged repetition. We wish to a) determine whether schizophrenic patients can display orienting response (OR) flexibility, responding to newly designated targets and ceasing to respond to newly designated nontargets; b) determine whether renewed hyporesponding can be averted with reminders of target relevance and repeated introduction of new targets; and c) compare schizophrenics with depressives and normal controls. Fifty schizophrenics (14 drug free), 50 depressives (20 drug free), and 50 normal controls receive four trial blocks involving the same sequence of 16 1000- or 2000-Hz tones delivered to either the right or left ear. A subsample of each group (N = 14) receives all blocks as a simple habituation series; others (N = 36) have to press a pedal for designated target signals (left ear or right ear, 1000 Hz or 2000 Hz), ignoring all nontarget tones. On each trial block, a new target signal is defined, and previous targets are discarded. Skin conductance and finger pulse amplitude analyses are presented. Both patient groups show enhanced ORs to newly relevant targets and ceased ORs to newly irrelevant former targets as well as normals. Both show OR decline with target repetition despite reminders and new targets.

The autonomic orienting response and CT scan findings in schizophrenia.

CT scan measures of prefrontal sulcal prominence, parieto-occipital sulcal prominence, ventricle-brain ratio (VBR), and third ventricle width (TVW) were examined in 24 schizophrenic patients who were grouped on the basis of their autonomic orienting response (OR) status. A two-component definition of the OR was used that required concordance across both electrodermal and finger pulse volume components for response status assignment. The nine OR responders had significantly greater TVW than the 15 OR nonresponders. Although OR responders had higher values also on the other CT scan measures, these differences were not significant. These findings are consistent with the possibility that OR responsiveness and nonresponsiveness are related to different pathological dimensions of schizophrenia.

Psychophysiological response patterns in college students with high physical anhedonia: scores appear to reflect schizotypy rather than depression.

The Chapman physical anhedonia (AN) and perceptual aberration (AB) scales were intended to identify high risk for schizophrenia. Although schizophrenic-like dysfunctions have been reported in association with each, the issue is clouded by possible relationships with depression. We recently reported psychophysiological patterns distinguishing depression from schizophrenia. Schizophrenics showed reduced orienting response (OR) to innocuous stimuli in both electrodermal (SCR) and finger pulse (FPV) components, normalizing in both to significant signals. Depressives showed deficient, non-normalizing SCR, but normal FPV, implicating SCR/cholinergic rather than OR deficits. 16 AN, 18 AB, and 17 control students received an innocuous (habituation) tone series followed by a significant (alternating-press) series. ANs displayed schizophrenic-like rather than depressive-like response patterns, but ABs showed no coherent pattern. Findings in ANs were somewhat attenuated compared with schizophrenics, perhaps reflecting the small percentage of schizophrenics-to-be in this risk group. The absence of clear deficit in ABs agrees with studies showing OR deficits to be associated with more negative symptoms in schizophrenia.

Orienting response research in schizophrenia: where we have come and where we might go.

This review and critique of orienting response (OR) research in schizophrenia examines the initial Western work, outlines current positions, and notes several areas in which further lines of research are needed. Discussion involves characteristics of schizophrenic patients who are OR nonresponders; OR nonresponding as a possible trait marker; the question of OR nonresponding in child patients; the association between negative symptoms and OR nonresponding as well as the possible existence of a specific subgroup marked by emotional withdrawal and cognitive disorganization; slow habituation as a prognostic index in high-risk children and adult acute patients; the need for research into defensive and startle responses as well as the OR, and possible interactions among them; electroencephalographic-autonomic differences in OR; and the need to explore the functional meaning of OR nonresponding in schizophrenia.

The effect of stimulus significance on relatively sustained (tonic-like) and relatively transient (phasic-like) aspects of electrodermal, heart rate, and eyeblink response.

To examine the influence of stimulus significance on more sustained as well as transient aspects of electrodermal, cardiac (HR), and eyeblink response, a 21-sec tone was sounded in one ear or the other. A click occurred during many tones, and a light followed offset by 9 sec. Four groups were studied: one pressed a pedal immediately on hearing any click; another only on click during tone in a specified ear; a third also responded only to the specified ear, but withheld press until the light; a fourth listened without any response. Results confirmed the important role of stimulus significance in each system whether between- or within-subject comparisons were made. Sustained responses were seen only when a significant signal was sought, involving in each case sustained HR deceleration, slowed blink rate, and heightened electrodermal level. Transient response to click and light also appeared only when there were significant signals. Response to tone-onset gave more ambiguous results. ANOVAs of response magnitude suggested that onset of nonsignificant tones might have elicited ORs, while binomial tests indicated these were not elicited with better than random frequency anywhere but on those trials occurring more frequently at the experiment's onset. Interpretations consistent with both the significance hypothesis and with a distinction between automatic and voluntary ORs can be made only here. Motor response had no effect on electrodermal or eyeblink response, and on HR was associated only with increased acceleration 1-2 sec after pedal-press. Studies using small motor responses to establish stimulus significance are therefore not likely to be substantially biased by the response itself.

A limiting factor in the "normalization" of schizophrenic orienting response dysfunction.

Forty schizophrenic patients, 40 non-schizophrenic patients, and 40 normal subjects were given 60 each alternating 1000- and 2000-Hz, 1-second tones at 60 dB. Half of each sample, the Press Group (PG), had to press a pedal to the high (low) target tone, ignoring the nontarget tone. The other half, the Nonpress Groups (NPGs), were given no reason to attend. Skin conductance response (SCR), finger pulse volume (FPV), and electroencephalographic (EEG) activity were recorded. NPG schizophrenic subjects were more often nonresponsive in both SCR and FPV than other samples, but less often responsive in EEG only when a 20 percent criterion of alpha blockade was used. Schizophrenic subjects showed greater consistency of OR nonresponsiveness in SCR and FPV, and nonsignificantly greater consistency in criterion alpha block, pointing to a deficit in orienting response (OR) rather than in peripheral response. When the targeted signal was given, schizophrenic subjects showed the same response as other groups in all systems. This was not due to an indiscriminate increase in reactivity, since response increase centered on the targeted signal itself in all groups. As the target signal was repeated, autonomic OR in schizophrenics declined sharply so that they again became underresponsive. Thus, OR "normalization" achieved by targeting significant signals is restricted to relatively early responsiveness. The rapid decline in autonomic OR may help explain differences in schizophrenic subjects between P300 and autonomic ORs to significant stimuli. Schizophrenic subjects were no different from controls in bilateral SCR or FPV asymmetry, but displayed less frequent criterion alpha blockade and reduced background alpha power in the left hemisphere. Each system showed a different pattern of bilateral asymmetry, reflecting complex, not well understood relations among these responses. This was further emphasized by the fact that skin conductance level (SCL) incremented over trials in PG subjects, reflecting sustained activation, while EEG background showed an increase in slower wave power, consistent with reports of increased drowsiness. The only drug effect seen was a lowering of SCL. Neuroleptics were associated with a flexible inhibitory control of SCL, permitting normal-like increment when circumstances required. Depressed patients' data suggested they might show heightened OR nonresponsiveness to innocuous stimuli which might not be subject to "normalization" by manipulation of stimulus significance; hence OR deficit might still differentiate schizophrenic from depressive patients.

An analysis of the skin conductance orienting response in samples of American, British, and German schizophrenics.

The existing literature dealing with the phasic orienting response (OR) in schizophrenia, examining, for the most part, the skin conductance component (SCOR), reports conflicting results with divergent implications for the nature of the attentional dysfunction in these patients. The present authors have contributed to that literature and to its divergencies. The present report addresses this issue by applying a common set of response definitions and uniform statistical-analytic procedures to the previously gathered electrodermal data obtained independently in each author's laboratory. A total of 14 studies is involved, drawn from six laboratories in the U.S.A., the U.K., and West Germany. Collectively, these studies examine chronic and acute schizophrenics, males and females, those receiving neuroleptic drugs and those not receiving them, recording SCOR from either (or both) hands using a variety of instruments and somewhat differing instructions and conditions, to both auditory and visual stimuli of different intensities and rise-time properties. The authors' purpose is two-fold. First, to determine whether some 'universal' dysfunction can be demonstrated across laboratories, conditions, and samples. Given the heterogeneous origins of these data such a finding would offer fairly strong evidence of 'real' dysfunction in schizophrenia. Second, where disagreement exists, to describe the scope and nature of the disagreement, and to articulate more clearly the findings on each side of a disputed area. One such 'universal' dysfunction emerged. Consistently, schizophrenics displayed an abnormally high incidence of nonresponsiveness, involving nearly 50% of the schizophrenic sample on average. The next most common finding is that many of the schizophrenics who display an SCOR often habituate faster than do nonschizophrenic responders. This was seen in a majority of the studies and laboratories, but conflicting evidence was presented by a minority. Evidence for a dysfunction simultaneously involving SCOR hypo- and hyper-responsiveness within schizophrenia was obtained, but in a minority of studies. The possible effects of neuroleptic drugs, stimulus intensity and rise-time factors, and differential significance evaluation on these findings was discussed. The possibility that schizophrenic dysfunction involves the input-facilitating OR but not input-attenuating 'protective' responses is examined. The correlates of hyporesponsiveness in schizophrenia, including physiological response patterns, clinical symptom patterns, and specific input deficiencies, is also examined. Several areas are noted where systematic research has only begun, and further study is particularly needed.

Bilateral skin conductance, finger pulse volume, and EEG orienting response to tones of differing intensities in chronic schizophrenics and controls.

Skin conductance (SCOR), finger pulse volume (FPV-OR), and EEG orienting responses were examined to repeated tones of either 60- or 90-dB intensity in chronic schizophrenics, nonschizophrenic psychiatric patients, and normals. SCOR reaffirmed previous findings with schizophrenics displaying significantly more frequent nonresponsiveness to 60-dB tones, and faster habituation among patients who did respond. Increased stimulus intensity decreased the incidence of nonresponsiveness to the level of controls, but did not alter the rapid habituation of schizophrenics. These results generalized fully to the FPV-OR, despite the independence demonstrated between SCOR and FPV-OR, but did not generalize to EEG response. There were no significant differences between schizophrenics and controls in EEG reactivity-only in background activity, particularly in a slowing of dominant alpha frequency in schizophrenics. Schizophrenics displayed the same degree of bilateral asymmetry as controls in both SCOR and EEG; there was no evidence of a specifically schizophrenic asymmetry. Schizophrenics nonresponsive in either SCOR or FPV-OR showed significantly greater Conceptual Disorganization and Emotional Withdrawal, and significantly less Excitement than responders in blind clinical ratings on the Brief Psychiatric Rating Scale. None of the findings could be attributed to the effect of neuroleptics. Comparisons between medicated and nonmedicated patients showed no drug-associated effect on any OR variable under study. Drug effects were apparent only in skin conductance level (SCL). Neuroleptics were associated with a significant reduction in SCL in both schizophrenics and nonschizophrenics, together with a flattening of an otherwise incrementing SCL among schizophrenics.

The orienting response and stimulus significance: further comments.

Siddle's (1979) assertion that the significance hypothesis is based on tautological argument regarding the effects of intensity decrease refer only to two papers which first suggested the need for research into determinants other than mismatch. Studies testing specific predictions followed in various laboratories, and it is their results that support the hypothesis. The hypothesis never depended on intensity decrease, and the charge of nonreplicability is incorrect. Siddle's argument concerning response stereotypy cannot account for the data showing response to significant 'novelty' coupled with nonresponse to nonsignificant 'novelty' in the same OR component, or for that showing consistent differences in various components between randomly selected groups. Arguments based on trait-lability are inadequate since tests of the lability hypothesis have confounded trait factors with the differences in stimulus assessment they hope to test. The significance hypothesis emphasizes stimulus information in the OR, significance serving to limit access to central processing channels to those signals whose information is relevant for the organism. OR components are seen as long-latency responses elicited after automatic early detection of uncertainty and significance, and reflect higher processing of significant information. A distinction between involuntary and voluntary phases of attention is acknowledged, but it is questioned whether OR components can be assigned to the former because of the frequent failure of 'automatic' ORs to innocuous stimuli, the long latency of most components, and failure to demonstrate structural differences between the classes of response.

Evidence of incomplete cortical modulation of autonomic responses in 11-to 16-year-old adolescents.

This study examines response differentiation in the sympathetically innervated skin conductance response (SCR). Differentiation in such systems has been ascribed to cortical inhibitory control over subcortical autonomic centers. Developmental study of such differentiation thus provides information on cortical development and the maturation of cortical control over subcortical centers. Previous investigators have focused on the simple level of differentiation involved in discriminating response on one side the body from that on the other. In such studies several investigators reported more diffuse response among young children; some reported adultlike differentiation by approximately age 10. The present study examines a more complex instance of differentiation, the quantitative modulation of response from a given site in order to produce SCR amplitudes proportionate to the information value of the eliciting stimulus. Relatively large amplitude SCRs elicited by imperative PRESS-SIGNALS of varying information value were studied, together with smaller SCRs elicited by NONPRESS-SIGNALS also varying in information value, in two adolescent groups, aged 11-16 years, and in a young adult sample. In contrast to earlier work, the present study demonstrates a continuing difference between adolescents and adults. Adults showed consistent differentiation, with SCR amplitude reflecting changes in stimulus information values for both PRESS- and NONPRESS-SIGNALS. Adolescents displayed differentiation only for SCRs elicited by NONPRESS-SIGNALS: Response to PRESS-SIGNALS did not reflect stimulus information values, even though reaction time data demonstrated that PRESS-SIGNAL information was being registered cortically. The degree of cortical control present in these adolescents, enabling them to display differentiated SCRs to NONPRESS-SIGNALS, would likely be sufficient to allow simple left-right discrimination, perhaps accounting for the "adultlike" reactions previously reported for this age group. The inability of the adolescents to sustain SCR differentiation when large amplitude responses were elicited by the PRESS-SIGNALS might reflect the inability of still immature cortical controls to cope with sizable sympathetic output. A "critical level" of sympathetic "arousal" may exist for adolescents in this age range, above which cortical inhibitory controls may become ineffective.