WEBVTT 1 00:00:01.980 --> 00:00:03.960 Welcome to module three. 2 00:00:03.960 --> 00:00:05.580 Chapter six in your textbook provides 3 00:00:05.580 --> 00:00:08.070 a really good introduction to toxicology, 4 00:00:08.070 --> 00:00:10.410 but in this presentation we'll take a closer look 5 00:00:10.410 --> 00:00:12.240 at dose response relationships 6 00:00:12.240 --> 00:00:14.730 that don't follow the traditional pattern, 7 00:00:14.730 --> 00:00:16.770 and hopefully reinforce some of the key takeaways 8 00:00:16.770 --> 00:00:17.703 for this module. 9 00:00:18.720 --> 00:00:21.180 I strongly recommend that you watch the two short videos 10 00:00:21.180 --> 00:00:25.200 about dose response before continuing with this presentation 11 00:00:25.200 --> 00:00:26.730 because this lecture will build upon 12 00:00:26.730 --> 00:00:29.313 the concepts presented in those videos. 13 00:00:32.910 --> 00:00:34.920 So let's start out with a reminder 14 00:00:34.920 --> 00:00:37.950 of a few key definitions in toxicology. 15 00:00:37.950 --> 00:00:39.510 First, it's always good to remember 16 00:00:39.510 --> 00:00:42.570 that toxins are substances of natural origin, 17 00:00:42.570 --> 00:00:45.183 while toxicants are synthetic substances. 18 00:00:46.290 --> 00:00:50.400 Next, a key definition in toxicology is the threshold. 19 00:00:50.400 --> 00:00:53.550 The threshold is the level above which effects will occur 20 00:00:53.550 --> 00:00:56.913 and below which no effects will occur for a given substance. 21 00:00:58.530 --> 00:01:02.370 The reference dose, often written as RfD, 22 00:01:02.370 --> 00:01:04.110 is the EPA's estimate 23 00:01:04.110 --> 00:01:07.410 of the daily lifetime dose of a substance 24 00:01:07.410 --> 00:01:10.740 that is unlikely to cause harm in humans. 25 00:01:10.740 --> 00:01:11.573 In other words, 26 00:01:11.573 --> 00:01:14.580 it represents the maximum acceptable daily dose, 27 00:01:14.580 --> 00:01:18.243 typically through an oral route of a toxic substance. 28 00:01:22.590 --> 00:01:25.650 Let's keep going with a few more definitions. 29 00:01:25.650 --> 00:01:30.330 The NOAEL is the no observed adverse effect level. 30 00:01:30.330 --> 00:01:31.770 So it's the highest dose 31 00:01:31.770 --> 00:01:36.750 at which there was not an observed toxic or adverse effect. 32 00:01:36.750 --> 00:01:39.870 This is the experimental equivalent of threshold, 33 00:01:39.870 --> 00:01:41.793 which we covered on the last slide. 34 00:01:43.290 --> 00:01:47.760 LOAEL is the lowest observed adverse effect level. 35 00:01:47.760 --> 00:01:49.800 In other words, it's the lowest dose 36 00:01:49.800 --> 00:01:53.523 at which there was an observed toxic or adverse effect. 37 00:01:54.960 --> 00:01:58.713 MTD is the maximum tolerated dose. 38 00:01:59.610 --> 00:02:00.480 And then finally, 39 00:02:00.480 --> 00:02:03.390 a monotonic dose response relationship 40 00:02:03.390 --> 00:02:08.390 is one where as the dose increases, so does the response. 41 00:02:08.520 --> 00:02:10.500 In other words, this is what is thought of 42 00:02:10.500 --> 00:02:13.383 as the typical dose response pattern. 43 00:02:18.600 --> 00:02:20.820 Not all substances follow 44 00:02:20.820 --> 00:02:23.638 the traditional dose response pattern. 45 00:02:23.638 --> 00:02:26.850 Nonmonotonic dose responses go against 46 00:02:26.850 --> 00:02:30.990 predictable or typical dose response patterns. 47 00:02:30.990 --> 00:02:33.780 With nonmonotonic dose responses, 48 00:02:33.780 --> 00:02:36.360 the dose response curve changes direction 49 00:02:36.360 --> 00:02:39.090 within the range of doses examined 50 00:02:39.090 --> 00:02:40.620 and can create unusual shapes, 51 00:02:40.620 --> 00:02:45.600 such as inverted U-shape, U-shapes, or multiphasic curves, 52 00:02:45.600 --> 00:02:47.763 as shown in this figure. 53 00:02:54.150 --> 00:02:56.670 This figure provides examples illustrating 54 00:02:56.670 --> 00:03:00.890 slightly more complicated nonmonotonic dose response curves 55 00:03:00.890 --> 00:03:03.690 at different portions of the dose response curve 56 00:03:03.690 --> 00:03:07.020 relative to the no observed adverse effect level, 57 00:03:07.020 --> 00:03:09.873 or the NOAEL, and the reference dose. 58 00:03:12.090 --> 00:03:15.990 In part A, circles indicate doses typically examined 59 00:03:15.990 --> 00:03:18.240 in conventional toxicity tests, 60 00:03:18.240 --> 00:03:20.673 which are used to calculate the reference dose. 61 00:03:21.630 --> 00:03:23.580 This figure shows the expected relationship 62 00:03:23.580 --> 00:03:25.500 between human exposure levels 63 00:03:25.500 --> 00:03:29.603 and the reference dose, as well as the NOAEL. 64 00:03:30.510 --> 00:03:33.090 So here you've got your reference dose. 65 00:03:33.090 --> 00:03:34.383 Here's the NOAEL, 66 00:03:35.520 --> 00:03:36.840 and then here's your LOAEL, 67 00:03:36.840 --> 00:03:40.590 the lowest observed adverse effect level. 68 00:03:40.590 --> 00:03:45.180 And then up here your maximum tolerated dose 69 00:03:45.180 --> 00:03:48.033 and then this is an overtly lethal dose at the top. 70 00:03:50.490 --> 00:03:54.153 No adverse effects are expected at human exposure levels, 71 00:03:55.320 --> 00:03:57.480 the reference dose or the NOAEL, 72 00:03:57.480 --> 00:03:59.340 if the NOAEL represents 73 00:03:59.340 --> 00:04:03.390 a true threshold for adverse effects. 74 00:04:03.390 --> 00:04:06.780 So these three would all have no response, 75 00:04:06.780 --> 00:04:08.943 if that holds true. 76 00:04:12.420 --> 00:04:14.868 In part B of the figure, 77 00:04:14.868 --> 00:04:19.260 nonmonotonicity is observed above the NOAEL. 78 00:04:19.260 --> 00:04:23.770 So here's the NOAEL, and we see a reaction above that 79 00:04:25.530 --> 00:04:27.480 at high levels of exposure. 80 00:04:27.480 --> 00:04:31.440 So the study that's mentioned down here, 81 00:04:31.440 --> 00:04:34.593 noted a couple different examples of this type of curve, 82 00:04:35.850 --> 00:04:38.580 including one study in male mice that were exposed 83 00:04:38.580 --> 00:04:43.580 to a chemical called Dichlorodiphenyltrichloroethane or DDT, 84 00:04:43.920 --> 00:04:45.333 during their development. 85 00:04:47.820 --> 00:04:50.010 In part C, 86 00:04:50.010 --> 00:04:55.010 the nonmonotonicity occurs between the reference dose here 87 00:04:55.080 --> 00:04:56.033 and the NOAEL. 88 00:04:57.111 --> 00:05:00.270 One example cited in the literature 89 00:05:00.270 --> 00:05:03.480 showed that 1.5 milligrams 90 00:05:03.480 --> 00:05:07.200 per kilogram per day of Permethrin 91 00:05:07.200 --> 00:05:09.510 altered dopamine transport in mice, 92 00:05:09.510 --> 00:05:13.170 whereas higher and lower doses were ineffective. 93 00:05:13.170 --> 00:05:18.009 So that's where you see this increase in response, 94 00:05:18.009 --> 00:05:21.693 that you don't see at both lower and higher doses. 95 00:05:22.890 --> 00:05:26.010 So the effects were observed above the reference dose 96 00:05:26.010 --> 00:05:27.363 and below the NOAEL. 97 00:05:29.310 --> 00:05:32.460 In part D, nonmonotonicity occurs 98 00:05:32.460 --> 00:05:35.370 at exposures below the reference dose. 99 00:05:35.370 --> 00:05:36.630 So here's the reference dose 100 00:05:36.630 --> 00:05:40.473 and you're seeing an increased effect at lower doses. 101 00:05:43.200 --> 00:05:45.090 Doses at or below the reference dose 102 00:05:45.090 --> 00:05:50.040 are rarely directly tested in conventional toxicity studies. 103 00:05:50.040 --> 00:05:53.370 Studies utilizing standard test guidelines 104 00:05:53.370 --> 00:05:56.250 typically aim to identify the NOAEL 105 00:05:56.250 --> 00:05:59.370 and then examine only three or four doses 106 00:05:59.370 --> 00:06:01.070 that are usually higher than that. 107 00:06:02.100 --> 00:06:06.390 So if nonmonotonic dose response curves 108 00:06:06.390 --> 00:06:10.383 are observed below the reference dose, as in case D, 109 00:06:11.550 --> 00:06:14.460 it would indicate that the reference dose 110 00:06:14.460 --> 00:06:18.660 and by extrapolation, the NOAEL, are scientifically flawed 111 00:06:18.660 --> 00:06:21.303 and insufficiently protective of public health. 112 00:06:22.200 --> 00:06:26.250 More than 30 such examples have been observed 113 00:06:26.250 --> 00:06:29.793 in human epidemiology studies and fall into this category. 114 00:06:31.470 --> 00:06:34.440 They provide evidence that human exposure levels, 115 00:06:34.440 --> 00:06:36.570 which are likely below the reference dose, 116 00:06:36.570 --> 00:06:39.270 can result in adverse health outcomes 117 00:06:39.270 --> 00:06:43.113 and PCBs are a good example that fall into this category. 118 00:06:46.890 --> 00:06:47.895 The important items 119 00:06:47.895 --> 00:06:50.370 that I want you to take away from this lecture 120 00:06:50.370 --> 00:06:52.500 are that the dose response relationship 121 00:06:52.500 --> 00:06:55.410 is a fundamental tool in toxicology 122 00:06:55.410 --> 00:06:58.230 that's used to determine how much of a substance it takes 123 00:06:58.230 --> 00:07:00.540 to cause harm in humans, 124 00:07:00.540 --> 00:07:02.250 as well as how much of a substance 125 00:07:02.250 --> 00:07:05.493 humans can be exposed to without causing harm. 126 00:07:06.570 --> 00:07:09.150 Not all substances have predictable 127 00:07:09.150 --> 00:07:11.100 or typical dose response patterns, 128 00:07:11.100 --> 00:07:14.640 which show that as the dose increases so does the effect. 129 00:07:14.640 --> 00:07:17.190 You don't need to remember any of these facts 130 00:07:17.190 --> 00:07:20.670 about nonmonotonic dose response curves 131 00:07:20.670 --> 00:07:22.740 that I covered in the last slide. 132 00:07:22.740 --> 00:07:25.860 Just be aware that some of these exist 133 00:07:25.860 --> 00:07:29.460 and that you can't always expect a specific agent 134 00:07:29.460 --> 00:07:31.833 to have a typical dose response pattern.